Acute promyelocytic leukemia (APL) is distinguished by the presence of a reciprocal translocation between chromosomes 15 and 17, or t(15;17).1 Depending on the country, APL usually accounts for between 5 and 12% of all acute myeloid leukemia (AML) cases,2 and is usually associated with disseminated intravascular coagulation (DIC), hemorrhagic syndrome and central nervous system involvement, along with typically acute leukemia complications, such as infections.3

From the discovery of the promyelocytic leukemia retinoic acid receptor (PML-RAR) alpha fusion protein, APL treatment was revolutionized by the introduction of the all-trans retinoic acid (ATRA),4,5 a vitamin A derivative that induces differentiation of immature promyeloblasts into mature granulocytes.6 Its combination with arsenic trioxide (ATO) is considered the first-line treatment of APL, able to induce a complete remission (CR) in ≥ 90% of patients, with a 2-year overall survival (OS) of 99%.7 More recently, ATO has been approved by the regulating organizations in both the USA and Europe for the treatment of newly diagnosed patients with low-to-intermediate risk APL.8

APL is associated with a high risk of early hemorrhagic death during induction, ranging from 3 to 11% in some studies.9,10 In developing countries, the mortality rate at induction was significantly higher (up to 32%).11 In order to narrow this gap, the International Consortium on Acute Promyelocytic Leukemia (IC-APL) developed a protocol with standardized supportive care and accessible drugs, which helped diminish the early mortality rate and improve the OS in developing countries, indirectly reducing the economic burden associated with the treatment of APL.3,12 Such a regimen is comprised of three phases: an induction phase (ATRA plus daunorubicin [DNR]), a consolidation phase (ATRA plus DNR, cytarabine [Ara-C] and mitoxantrone [MTZ]) and a maintenance phase (ATRA plus methotrexate [MTX] and 6-mercaptopurine [6-MP]).3,12

The IC-APL protocol has provided excellent clinical results in the treatment of APL, with a 2-year OS in adults, initially achieving only a 50% OS, with an induction mortality rate reaching 30%11 and increasing the OS to 80% and reducing mortality by half, after undergoing some modifications.3 Additionally, arsenic trioxide (ATO) has shown adequate responses with low toxicities in developing countries,13 however, it is not reimbursed by the public health system in Mexico and its cost is considerably high.

The objective of this study was to perform a cost-effectiveness analysis (CEA) and a cost-utility analysis (CUA) of the modified IC-APL protocol in Mexico, comparing it to the costs of the first-line treatment ATRA plus ATO in other countries.

In our study conducted at a tertiary referral center in Mexico City, we found that the total median cost of the APL treatment, using the modified IC-APL protocol, was $21,523 USD, with a 94% CR and a CEA of $227 USD (per each percentage of CR). Medical costs in our study represented most of the total median cost of treatment (57%). The ICER and ICUR were lower compared to Italy, the USA and Canada for the former, and the USA and Canada for the latter, since the Italian report did not include their QALY.

According to this study, although ATRA plus ATO regimen patients have fewer clinical adverse events and shorter duration of treatments, compared to regimens with ATRA plus chemotherapy, which lead to lower medical costs, the medical costs of the modified IC-APL protocol were higher than Italy's, but lower than USA's and Canada's ($12,369 USD, $9530 USD, $22,837 USD and $44,898 USD, respectively).4,14,23 Additionally, hospitalization during induction with the modified IC-APL protocol is longer, when compared with to ATRA plus ATO, leading to higher medical costs in Mexico, compared to the reported costs in Italy.

Chemotherapy costs of the modified IC-APL protocol in Mexico represented 42% of the total median costs and were found to be lower, compared to those reported in the USA, Italy, and Canada (85.2, 82 and 75.9%, respectively).4,14,23 Access to the drugs in the modified IC-APL protocol is easy, contrary to ATO, whose estimated cost ($391 USD for each 10-mg vial) renders it more difficult to attain.23 In addition, the current recommendations include the use of ATRA plus ATO only for low-to-intermediate-risk patients, as comparative economic studies from Canada and Italy did not include high-risk patients.4,14,23 Even considering that 15% of our patients were high-risk patients and received Ara-C during consolidation, chemotherapy costs were found to be lower, compared to these countries. Regarding the incremental cost-effectiveness ratios (ICERs), in order to achieve the same CR rates of the ATRA plus ATO protocols, an increase of $6497 to $19,133 USD would be required.4,14,23 Concerning the comparison of the ICER to the ATRA plus chemotherapy protocols, an even higher cost is represented, since the CR rates are similar.7,19,20

In spite of our results reporting lower QALY, when compared to those of the USA (6.1 years vs 14.33 and 8.58 years in the ATRA plus ATO and ATRA plus chemotherapy protocols, respectively) and of Canada (14.58 years in the ATRA plus ATO protocol), the cost-utility index of the modified IC-APL protocol is the lowest ($3500 USD pear QALY). These results indicate that for each QALY, an estimated cost of $3500, $9502 and $8454 USD is required in Mexico, the USA and Canada, respectively. According to the incremental cost-utility ratios (ICURs), in order to obtain the same QALY of the ATRA plus ATO protocols, an increase of $11,979 to $13,955 USD would be required.14,23

This study has several limitations. First, all medical visits (hematologist or other specialists) are not routinely charged for at our institution, consequently contributing to lower medical costs during patient hospitalizations. Second, the years of analysis among studies used for comparison were different and could probably have derived a cost difference due to the inflation rate. Third, patients included in this analysis were evaluated and treated from 2007 to 2013, when the exchange rate of pesos to dollars ranged from $9.1 to $15.23, but we used a more representative exchange rate of 20.76 (from November 12, 2016) to present updated costs. However, to overcome these limitations, this model was based on data taken directly from medical records for each individual, which renders highly accurate medical and chemotherapy costs.

Estimating the financial impact of including all drugs of the modified IC-APL treatment regimen on the drugs supplied by the national public health system is critical to understand the net benefit to clinical outcomes and QALYs. Further research is needed to establish the cost-effectiveness at other referral centers in our country to standardize treatment and analyze the benefit of the IC-APL in other hospital settings. Considering the similar response rates among treatment protocols, the lower cost and the easy access to the modified IC-APL regime in settings, such as Mexico, this regimen is a cost-effective and cost-useful protocol that should be considered for all patients recently diagnosed with APL.

This study was approved by our local Ethics Committee, as was the original study by Crespo-Solís et al., which complied with the principles established in the Declaration of Helsinki for research involving human subjects.

The authors declare no conflicts of interest.