Cost Structure and Clinical Outcome of a Stem Cell Transplantation Program in a Developing Country: The Experience in Northeast Mexico

The costs of laboratory tests, medical procedures, chemotherapy drugs, other drugs, and hospitalization of patients receiving an allogeneic hematopoietic stem cell transplantation (HSCT) were scrutinized to calculate the total cost for each patient and the median cost for the procedure and to assess its clinical outcomes. The results show that HSCT is an affordable option for hematological patients living in a developing country.

Abstract

Background and Objective.

Hematopoietic stem cell transplantation (HSCT) in developing countries is cost-limited. Our primary goal was to determine the cost structure for the HSCT program model developed over the last decade at our public university hospital and to assess its clinical outcomes.

Materials and Methods.

Adults and children receiving an allogeneic hematopoietic stem cell transplant from January 2010 to February 2011 at our hematology regional reference center were included. Laboratory tests, medical procedures, chemotherapy drugs, other drugs, and hospitalization costs were scrutinized to calculate the total cost for each patient and the median cost for the procedure. Data regarding clinical evolution were incorporated into the analysis. Physician fees are not charged at the institution and therefore were not included.

Results.

Fifty patients were evaluated over a 1-year period. The total estimated cost for an allogeneic HSCT was $12,504. The two most expensive diseases to allograft were non-Hodgkin lymphoma ($11,760 ± $2,236) for the malignant group and thalassemia ($12,915 ± $5,170) for the nonmalignant group. Acute lymphoblastic leukemia ($11,053 ± 2,817) and acute myeloblastic leukemia ($10,251 ± $1,538) were the most frequent indications for HSCT, with 11 cases each. Median out-of-pocket expenses were $1,605, and 1-year follow-up costs amounted to $1,640, adding up to a total cost of $15,749 for the first year. The most expensive components were drugs and laboratory tests.

Conclusion.

Applying the cost structure described, HSCT is an affordable option for hematological patients living in a developing country.

Implications for Practice:

This article describes in detail the strategy for performing hematologic transplantation at a public institution caring for uninsured patients applying an in-house cost-efficiency model that maximizes scarce financial resources. It provides individual costs for standard drugs and therapeutic, as well as laboratory, procedures used during the intervention. The results are important because they convey the message that this type of transplant can be made at affordable costs for diverse hematologic diseases without requiring expensive infrastructure, exemplifying how good clinical results, similar to those in advanced institutions in developed countries, can be reached with adequate planning and an experienced team.

Introduction

Hematopoietic stem cell transplantation (HSCT) from the peripheral blood has virtually replaced classic bone marrow transplantation. The advantages of this procedure include faster hematological and immunological reconstitution, easier stem cell harvest, lower antibiotic treatment courses, shorter hospital stay, and lower risk and discomfort for the donor. Several of these factors have contributed to considerably lower the cost of the procedure [1].

In developing countries with finite health care resources, survival of a HSCT program depends directly on its cost and affordability, which is even more critical for public hospitals caring for uninsured patients. It is therefore essential for these countries to develop a transplant structure based on high efficiency, financing maximization, and constant improvement leading to detection of cost saving opportunities if the HSCT program is to thrive [2]. This requires that the institution and transplant team implement policies leading to effective cost lowering and cost containment without affecting efficiency to make the intervention affordable for most of the population [3].

The costs of HSCT can be categorized as direct, indirect, or intangible [4]. Direct costs include the “hotel costs” during hospital stays, which include inpatient days, nursery, medical assistance, laboratory exams, monitoring procedures, drugs, mobilization of stem cells, blood products, donor selection (HLA typing), cell recollection (apheresis), quality control (CD34+ counting, chimerism studies), consumables, and depreciation of equipment. This categorization should also address the costs to families, a matter of special importance in the pediatric context, as in children with cancer, for whom this cost has been estimated to amount to one third of after-tax family income [4].

The cost of a health care intervention depends on whether the perspective is that of the patient (or family), provider, payer, employer, or society. Indirect costs derive from “the loss of a person’s ability to use life in a productive way, employment or some role valued by society or the person because of the illness.” Intangible costs are those of pain and suffering because they are not quantifiable in terms of cost-benefit [5]. For an adult patient who is the family provider, the inability to continue working will severely limit family income. For children, transplant expenses normally involve the allocation of at least one third of the household income [6], with this remarkably affecting the whole family’s quality of life.

Transplant patients can develop the usual complications of the aplastic phase following HSCT and at engraftment: mucositis, bleeding, febrile episodes with moderate or severe infection, graft versus host disease (GVHD), and others that require the use of antibiotics, antifungals, blood transfusion, and immunosuppressive treatment. All these conditions notably raise the cost of the procedure, causing uninsured patients, even those from developed countries, to be unable to afford a HSCT [7].

Peripheral HSCT is a complex, high-cost therapeutic intervention that requires a sophisticated hospital infrastructure, a hematology team with specific training and transplant experience, and modern technology to successfully fulfill every step of the process [8]. For less developed countries with health systems lacking the necessary tools to support the increasing number of patients that require a hematopoietic stem cell transplant, the need to lower the cost of HSCT is critical. In this report, we describe the different strategies and components of a successful HSCT program at a hematology reference center of a public university hospital in northeast Mexico.

Materials and Methods

Every adult and child patient receiving a related allogeneic or autologous HSCT from January 2010 to February 2011 at the Hematology Department, Internal Medicine Division of the Dr. José E. González University Hospital of the Autonomous University of Nuevo León in Monterrey, México was included. To determine the immediate costs of HSCT, the intervention was divided into five cost components: laboratory tests, medical procedures, chemotherapy drugs, other drugs, and transplant team and hospitalization costs. Detailed prices for each item used were registered per patient. To establish the cost of 1 year of treatment, the costs for 1 year of follow-up and out-of-pocket expenses were also included. The total cost was calculated by adding the costs of all these categories. Costs are reported in U.S. dollars. Subcutaneous granulocyte colony-stimulating factor (10 μg/kg per day) was given to the sibling donors or the patients on days −5 to 0, and 1 or 2 apheresis procedures were planned according to CD34+ cell counts with a Baxter C-3000 PLUS machine (Baxter Healthcare, Deerfield, IL, http://www.baxter.com), an AMICUS (Baxter Healthcare), or a COBE-Spectra (Gambro, Lakewood, CO, http://www.gambro.com/usa) device using the Spin-Nebraska protocol [9]. The endpoint of collection was the processing of 5,000–7,000 mL of blood/m² in each apheresis procedure, providing a total amount of at least 2 × 10⁶ CD34+ cells per kg of body weight of the recipient. The method of nonablative conditioning used in allogeneic HSCT consists of 4 mg/kg oral busulfan given on days −6 and −5; 350 mg/m² cyclophosphamide given i.v. on days −4, −3, and −2; and 30 mg/m² fludarabine given i.v. on days −4, −3, and −2. In patients with very severe aplastic anemia, busulfan was not used, and the cyclophosphamide dose was doubled from days −4 to −1 oral cyclosporin A (CyA) 5 mg/kg starting on day −1, and 5 mg/m² methotrexate was given i.v. on days +1, +3, +5, and +11. CyA was continued through day 180, with adjustments to obtain serum CyA levels of 150–275 ng/mL, and then tapered over 30–60 days. If GVHD was present, CyA was tapered over longer periods, and steroid was added. Ondansetron (1 mg i.v. every hour for 4 hours after i.v. chemotherapy), an oral quinolone, and an azole were used in all patients until granulocytes were >500 × 10⁶/liter for 3 consecutive days. The peripheral blood stem cell (PBSC) apheresis products were infused on day 0 [10]. Patients received chemotherapy at the outpatient clinic and were discharged after the procedure. All patients were examined daily at the outpatient transplant clinic until engraftment and had a caregiver at home or at a temporary residence that took care of food preparation, assisted in personal hygiene, controlled the scheduling and dosage of prescribed oral medication, and was alert to any complication that required medical care.

As a fundamental part of making HSCT an affordable procedure for noninsured patients, most of the hospitalization and the medical team costs are absorbed by our institution so that patients pay a standard fee for these services; therefore this cost was considered a constant at $1,200. Out-of-pocket expenses including housing, transportation, meals, and other were estimated at $1,605 for the patient and one additional family member/caregiver.

Descriptive statistical analyses for costs were carried out using SPSS software, v. 17.0 (IBM Corp., Armonk, NY, http://www-01.ibm.com/software/analytics/spss). For analysis, the patients were divided into those with malignant and nonmalignant diseases and divided into adults and children. Continuous variables were tested for normal distribution with the Kolmogorov-Smirnov test and compared by Student’s t test or the Mann-Whitney U test, depending on normal or not normal distribution. Pairs of groups were compared using the Mann-Whitney U test; a p value ≤ .05 was considered statistically significant.

Results

The sample group consisted of 50 patients, 30 men (60%) and 20 women (40%); 35 were adults (70%), and 15 were children (30%). Among these individuals, 12 different diagnoses were observed, as shown in Table 1, with acute lymphoblastic leukemia and acute myeloid leukemia being the most common with a 22% incidence or 11 cases each. In total, 37 patients (74%) had malignant disease, whereas 13 patients (26%) had a nonmalignant illness. The overall survival of patients was 67% at 36 months.

Table 1.

Cost distribution by specific diagnosis in patients receiving a hematopoietic stem cell transplant

Thirteen patients died (26%): 7 as a result of relapse, 1 as a result of chronic GVHD, 2 as a result of sepsis, and 3 as a result of nonrelated diseases. Engraftment occurred in all 50 patients; 6 developed acute GVHD (in 2 cases grade II–IV), whereas 12 patients developed chronic GVHD (in one case the disease was extensive).

The median of the cost for an allogeneic transplant was $12,504, compared with $8,528 for the autologous procedure. Median number of inpatient days was 6 for allogeneic versus 4 in the autologous group, accounting for 11% of the total cost, $1,375 for allogeneic transplants, and $935 for autologous transplants. Cost components were determined per unit and grouped into laboratory test and processing of hematopoietic stem cells, additional procedures and materials (Table 2), processing requirements and conditioning regimen drugs (Table 3), and chemotherapy drugs (Table 4). Depending on the requirements for each diagnosis, malignant or nonmalignant, and the age group, pediatric or adult, an estimation of the HSCT total cost was generated (Fig. 1). The two more expensive diseases to allograft were non-Hodgkin lymphoma ($11,760 ± 2,236) for the malignant group and thalassemia ($12,915 ± 5,170) for the nonmalignant group (Fig. 2). No significant differences were observed between adults and children for medical procedures, chemotherapy drugs, other drugs, and hospitalization, but a difference was noted for laboratory costs, which were higher for the pediatric group ($1,209 ± 975 vs. $1,061 ± 708; p = .044) (Fig. 1). It should be noted that for the pediatric group, the cost differed when the cord blood unit came from a cord blood bank in Mexico, covering only the transportation fee of $500, compared with a cord blood unit from another country, which increased the cost to $25,000 (these cases were not included in the cost analysis). Chemotherapy costs were significantly higher in the malignant disease group, with a mean of $1,007 ± 204 compared with the nonmalignant group $810 ± 200) (p = .004). For all the other components of the procedure, a significant difference was not documented. Out-of-pocket expenses were, on average, $1,605, including a month of housing, transportation, and food for the patient and one caregiver.

Table 2.

Unitary cost for laboratory tests and other materials and procedures needed for hematopoietic stem cell transplant

Table 3.

Unitary costs for processing the hematopoietic stem cell transplant and the conditioning regimen drugs

Table 4.

Unitary costs for chemotherapy drugs

Figure 1.

Hematopoietic stem cell transplant cost comparison for nonmalignant vs. malignant disease and pediatric vs. adult for each specific cost component.

Figure 2.

Hematopoietic stem cell transplant total cost, in U.S. dollars, for each specific diagnosis represented by its mean and standard deviation.

Abbreviations: AA, aplastic anemia; ALL, acute lymphocytic leukemia; AML, acute myeloid leukemia; BAL, biphenotypic acute leukemia; CGL, chronic granulocytic leukemia; HL, Hodgkin lymphoma; LHC, lymphohistiocytosis; MDS, myelodysplastic syndrome; MM, multiple myeloma; NHL, non-Hodgkin lymphoma; NPH, nocturnal paroxysmal hemoglobinuria; TLS, thalassemia.

Discussion

Intending to offer an alternative to the various economical restrictions previously described, some investigators propose cost containment protocols for HSCT. Among them, a group of Mexican investigators has developed a successful model to lower the cost of the procedure [11]. This model uses strategies to optimize available resources with the two most important being on an outpatient basis and a nonmyeloablative HSCT [12–14]. We changed the primary locus of care from inpatient to outpatient, which resulted in notable cost savings for low-risk patients, whereas the reduced intensity, nonmyeloablative conditioning approach reduced the number, duration, and severity of infections secondary to neutropenia and the need for blood product transfusion; in addition, the less intensive immune prophylactic scheme for GVHD reduces the medium and long-term cost by avoiding antithymocyte globulin therapy [15]. Advances in the care of these patients have increased their long-term survival and reduced death related to the grafting procedure, organ damage, infections, and severe acute GVHD [16]

By using these strategies, the number of allogeneic transplants in Mexico has increased remarkably in recent years [17], making it possible to use this valuable therapeutic tool for patients with malignant and benign hematologic diseases [12, 18].

In developing countries, most patients that require a HSCT are not able to choose between transplant modalities; they undergo either a HSCT based on a lowering-cost scheme or conventional therapy, which frequently offers a reduced opportunity for curing the primary disease [19]. The goal of this study was to analyze the cost structure of the HSCT program model developed over the last decade at the Hematology Service of the Dr. José E. González University Hospital of the School of Medicine of the Universidad Autónoma de Nuevo León, in Monterrey, Mexico; to compare it with HSCT programs in developed countries; and to evaluate the clinical outcomes.

The costs of HSCT in the world vary considerably, and a single representative estimate of the costs of allogeneic transplant cannot be derived; however, in centers in the U.S., the median cost of allogeneic HSCT for reduced-intensity conditioning was $80,499 to $84,824 dollars [20, 21], and in France, the median cost was €78,700 ($109,000) for one center [22]. The factors associated with increased costs were hospitalization, treatment of complications, and advanced-stage disease. We found an additional estimated cost of $1,640 for 1 year of treatment, including laboratory tests, drugs, and follow-up visits.

Among recipients of allogeneic HSCT, costs vary by donor source and conditioning regimen intensity, ranging from $80,499 to $137,564 in more contemporary studies with a median cost of $137,112 for myeloablative conditioning HSCT and of $84,824 for reduced-intensity conditioning (RIC) HSCT [20]. Saito et al. [21] found a similar pattern when examining costs over 1 year post-transplantation, reporting a median 1-year cost of $128,253 for myeloablative HSCT and $80,499 for RIC HSCT. In contrast, we reduced this cost to approximately $12,500 in adults and under $13,000 in children.

Some studies in different countries had similar findings to those reported in the U.S. studies. For example, in a single-institution study in Sweden, the cost of related donor transplantations was €129,133 ($179,000) versus €160,658 ($220,000) with unrelated donor transplantations. Another example of these variations in cost is Thailand. In a single-institution study, a cost of €22,593 ($30,000) for allogeneic HSCT was documented compared with €24,171 ($33,000) [23]. Contrasting findings were observed in a French study compared with the U.S., because the median cost of myeloablative transplantations in France is lower than for RIC transplants (€74,900 vs. €78,700) [22].

Literature dealing with HSCT costs in developing countries is scarce, and transplantation has been considered economically unaffordable for most patients living in these countries. This critical treatment option remains out of reach for a high percentage of patients in developing countries, where only a few institutions have the facilities, medical expertise, and resources to perform it; most uninsured families cannot afford it. Studies around the world have calculated the total cost for HSCT, and some have tried to make this procedure more affordable, as in our case [3]. We found important differences when comparing the cost of HSCT at our center with other reports from developed countries (Table 5).

Table 5.

Cost comparison among selected medical centers for allogeneic hematopoietic stem cell transplants for adults and children

A report on transplants for children from Spain showed that major determinants of overall costs for both allogeneic and autologous groups were a total body irradiation (TBI)-based conditioning regimen, days of hospitalization, and number of transfused platelets, with an estimated cost of $7,895 [28], compared with $2,840 for the conditioning regimen at our center, where TBI is not part of the conditioning. Another report on pediatric allogeneic HSCT found that total cost savings of $1,600 was related to lower costs of supportive items including blood products, parenteral nutrition, and antibiotics. Monitoring and hospitalization costs were significantly lower for the PBSC transplant (PBSCT) group in comparison with the bone marrow transplant (BMT) group, with savings of $354 and $2,686, respectively [29].

When comparing PBSCT transplant costs with BMT, the total was $18,304 lower for allo-PBSCT, with lower costs during recovery, specifically for hospitalization, platelet products, hematopoietic growth factors, leukapheresis, parenteral nutrition, supportive care agents, supplies, and antibacterial agents. Median harvest costs, however, were significantly higher for allo-HSCT: $6,688 versus $4,262 for allo-BMT (p = .05) [25].

Other studies have concluded that there is no difference between HSCT and BMT costs [26]. The incremental costs of G-CSF and apheresis were offset by savings in the surgical procedure. Costs attributable directly to the recipient that were incurred after day 0 did not differ between the groups. This is expected because the major determinants of those costs (antibiotics and hospitalization) are almost the same for PBSCT and BMT patients [26].

Strategies proposed for optimizing the cost of HSCT include the use of a less expensive conditioning regimen, a tailored number of apheresis sessions, elimination of ganciclovir and IgG, optimized transfusion of blood products, diminished number of donor lymphocyte infusions, and outpatient conduction when possible [17, 26]. Outpatient conduction is important because hospital inpatient days are the main determinant of high cost [24, 31].

The cost of HSCT at our center for allo-HSCT is $12,504 in adults and $12,950 in children, whereas the 1-year total cost, including follow-up and out-of-pocket expenses, was $15,749. In several studies from developed countries the cost of HSCT has been reported from $24,250 to $63,221 for adults and $14,046 for children [29], which is out of reach for most of our uninsured patients. Previous studies performed in the Mexican population found a HSCT cost of $18,000 for inpatient, compared with $8,000 for the outpatient-based transplant method [3, 17, 32]. Recently, the median 100-day total cost in the U.S. was reported. For allogeneic HSCT, it was $203,026. The majority of costs (47.5%) occurred during the initial transplant hospitalization [31].

Out-of-pocket expenses can significantly impact care and adherence among cancer patients. Distance from the transplant center, the need to relocate closer to the center and availability of support and resources both at home and locally around the center are important determinants of out-of-pocket costs. In one study, median out-of-pocket expenses during the inpatient period were $849.35 for caregivers who stayed in local accommodations and $181.15 for caregivers who stayed in the patient’s hospital room [33]. In another study, the median out-of-pocket and indirect costs for caregivers were $382 and $2,520, respectively, for a median patient hospital stay of 15 days [34]. We found average out-of-pocket and indirect costs of $1,605 per month, covering 1 month housing outside the hospital, meals, and transportation for the patient and one caregiver.

Costs related to hospitalization were the major contributors across the studies, and cost associated with initial hospitalization for HSCT was the main driver of total cost in the first 100 days post-transplantation [35]; medical staff costs, room and board, pharmacy, laboratory services, radiology, and blood products were the major cost contributors [36, 37]. Recently, in a study of HSCT with RIC at 2 institutions, it was found that significant predictors for lower costs for the first 100 days included a diagnosis of lymphoma/myeloma and use of human leukocyte antigen-matched related donors, whereas grade II–IV acute GVHD was associated with higher costs [38].

At our center, the higher cost components were drugs and laboratory tests, whereas hospitalization costs were minimal at a median of $1,153 (Fig. 2). Complications also play a major role in cost and tend to be associated with the duration of hospitalization, raising the cost by an average of $20,228 per complication [35].

We identified the most representative cost-lowering factors that make our HSCT affordable for most patients: the nonmyeloablative conditioning scheme, an outpatient transplantation method, a fixed low hospitalization fee, and the waiving of medical fees; in comparison, at other centers, the median of inpatient days represented 40% of the total cost, whereas total body radiation accounted for 12%, conditioning regimen accounted for 9%, and specialist fees accounted for 17% of final costs [27]. At our center, inpatient days represent 11% of the total cost, amounting to $1,375 for allogeneic and $935 for autologous transplantation, and the nonmyeloablative conditioning scheme accounted for 9%; there is no transplant team fee, and hospital inpatient charges are financed with the support provided by local and federal government funds allocated to us at our public institution; thus these conditions contribute to make HSCT an affordable and available procedure for low-income, uninsured patients. On the other hand, it has been documented that a disadvantage of HSCT after RIC is that the initial cost savings associated with nonmyeloablative conditioning regimens is offset by the higher costs of later complications and readmissions [22], which was not the case in our group. The main limitations in our study are a small sample size and heterogeneity in the diagnosis of grafted patients, whereas a robust case per case cost analysis, including out-of-pocket and 1-year follow-up costs, constitute important strengths.

Conclusion

Based on our experience during the last 15 years allografting patients suffering different hematological diseases at a public university hospital caring for low-income patients, we foresee the efficient application of HSCT to every low-income social group completed in an outpatient basis that is well-tolerated by the elderly and by patients with associated comorbidities, easily adapted to HLA disparity between donor and receptor, capable of eliciting a graft versus malignancy effect, causing minimal GVHD, and giving the maximum possibility of cure to patients who are not curable with other therapeutic methods [39, 40].

Author Contributions

Conception/Design: José Carlos Jaime-Pérez, Alberto Carlos Heredia-Salazar, Homero Gutiérrez-Aguirre, David Gómez-Almaguer

Provision of study material or patients: Olga G. Cantú-Rodríguez, David Gómez-Almaguer

Collection and/or assembly of data: César Daniel Villarreal-Villarreal

Data analysis and interpretation: José Carlos Jaime-Pérez, Alberto Carlos Heredia-Salazar, Homero Gutiérrez-Aguirre, César Daniel Villarreal-Villarreal

Manuscript writing: José Carlos Jaime-Pérez, Alberto Carlos Heredia-Salazar, Olga G. Cantú-Rodríguez, Homero Gutiérrez-Aguirre, César Daniel Villarreal-Villarreal, Consuelo Mancías-Guerra, José Luís Herrera-Garza, David Gómez-Almaguer

Final approval of manuscript: José Carlos Jaime-Pérez

Disclosures

The authors indicated no financial relationships.