Acute promyelocytic leukemia (APL) is a distinct subtype of acute myeloid leukemia (AML), most common in young adults, characterized by the accumulation of neoplastic promyelocytes in the bone marrow or/and peripheral blood.1 Cytogenetically, APL is identified by a balanced reciprocal translocation between chromosomes 15 and 17, which results in the fusion between the promyelocytic leukemia (PML) gene and retinoic acid receptor-α (RARα) gene, that can be identified by modern molecular techniques, such as the reverse transcription polymerase chain reaction (RT-PCR) for t(15;17).2 Immunophenotypically, APL cells share certain features with normal promyelocytic cells, however, APL cells express abnormally low levels of CD15 and weak or variable CD117.3,4

Clinically, APL represents a medical emergency, with a high rate of early mortality often due to a hemorrhage from typical coagulopathy associated with APL (TC-APL), low platelet count and/or hyperfibrinolysis.5,6 The prompt identification of APL, rapid target treatment and major support measures to avoid severe bleeding are important for good response rates.1

The introduction of all-trans retinoic acid (ATRA), in 1987, changed the treatment of APL.7,8 The use of ATRA, combined with anthracycline-based chemotherapy for induction and anthracycline-based chemotherapy, with or without cytarabine arabinoside (Ara-C) in consolidation, depending on the risk level, is still considered the standard-care treatment for APL.5,9–11 Arsenic trioxide (ATO) has been shown to be highly effective in APL and was initially tested in patients with relapse after ATRA and chemotherapy, but recent studies demonstrated the success of chemotherapy-free therapy (CFT) with ATO plus ATRA in first-line therapy in low- and intermediate-risk groups.12–14

The incidence of APL in Latin America is slightly high (20–25%), compared to North American and Northern European countries (10–15%), and some particularities of this disease must be studied.15,16 Some cases are still at high risk of death, especially early death (ED) and a better understanding of the clinical and biologic factors involving APL is needed to correctly identify and treat these cases.5,17,18 This retrospective study reported the clinical features and outcomes of forty-four consecutive newly diagnosed young adult APL patients, diagnosed between January 2001 and July 2013.

Many efforts have been made to identify prognostic markers for death in APL and make it a curable disease.1,5 The white blood cell count is a well-known important prognostic factor, described by the Programa para el Estudio de la Terapéutica en Hemopatía Maligna (PETHEMA) and Gruppo Italiano Malattie e Matologiche dell'Adulto (GIMEMA) cooperative groups in 2000, which provides guidance for treatment.20 Even as a retrospective study with a limited number of patients, the data confirmed the slightly higher incidence of APL in the Latin American population and reflected the results of other studies.

The population of the present study includes young adult patients, the majority of whom were at intermediate and high risk (84.1%), and 59.1% had a laboratory coagulopathy at diagnosis, which compromised the outcome. APL is frequently associated with TC-APL, which leads to a high mortality rate, especially early mortality.5 It is known that the prolongation of PT and aPTT, associated with thrombocytopenia and leukocytosis, are risk factors for severe bleeding and possible death. Patients at high risk for bleeding should be managed more aggressively.21,22

Many articles are trying to find new prognostic factors, such as the hemoglobin count, blast count,23 expression of CD34 by immunophenotyping,24 presence of FLT3 mutations,6,25 short bcr3 type PML-RARα fusion gene,26 ACAs,27 severe bleeding, or hypogranular APL,28 and to discover whether these new factors indeed have any influence on APL.

The association of reciprocal translocation t (15;17) with other ACAs has been established in many studies, but this has not happened for any independent influence on the outcome.25 The incidence is around 10–25 % of ACAs in APL.25 The FLT3-ITD occurs in 12–38 % of all APL patients and the FLT3-D835, in 2–20%.6,23 The FLT3-ITD and D835 mutations occurred in 17 patients and two (4.5%) of them were positive for FLT3-ITD (one had hypogranular APL, bcr3 transcript, was at high risk, and suffered early death). The statistical analysis was difficult because of the low number of patients. Usually, FLT3 was reported to worsen prognosis and to be associated with leukocytosis and the hypogranular subtype.6 However, more studies need to be carried out with the FLT3 mutations and ATO therapy as first line to observe the responses.

CD34 is a type I transmembrane glycophosphoprotein expressed on hematopoietic precursor cells in the early stages of differentiation. In APL, CD34 expression is clinically related to leukocytosis and hypogranular APL, but there is no clear association with the outcome.24 In this study, the CD34 expression was observed in 12 (27.3%) patients (Table 1). A simple analysis showed an association with death and CD34 expression, but this was not confirmed in a multivariable logistic regression analysis, reducing the power of this prognostic factor, however, the low number of patients in this study may have influenced this analysis.

APL therapy has improved dramatically over the past three decades, leading to a significant increase in the OS.29 This study presented a good OS rate (82.7%); it was carried out in a developing country by a teaching hospital fully funded by public resources. The early use of ATRA is a key factor contributing to a positive outcome and the medication may be administered as early as in the emergency room, even before a definitive diagnosis. The role of properly trained general practitioners and emergency physicians, as well as laboratory staff, is crucial for APL cases to be quickly recognized.

The introduction of the use of ATO for relapsed cases at the center where this study was performed, in 2008, changed the evolution of these patients with better response rates. As seen in many papers, the use of ATO has been a new target for therapy in APL.17,24

The International Consortium on Acute Promyelocytic Leukemia (IC-APL) was established in 2005 as an initiative of the International Members Committee of the American Society of Hematology (ASH). Its purpose was to create a network of institutions in developing countries for the exchange of experience and data and to receive support from well-established cooperative groups in the Unites States and Europe. After IC-APL was created, life expectancy of APL patients increased by 30%, which shows that this cooperation was essential for the increase in positive outcomes.18 However, early death, late diagnosis and relapse remain problems that need to be identified and avoided.17 In an American study by Park30 2011 with 1,400 APL patients, the overall ED was 17.3% between 1992 and 2007, even after the introduction of ATRA therapy, which corroborates the high ED rates (16.0%) in the present study. As can be seen in the Cox multivariate regression, the factor significantly related to death was severe bleeding, which was responsible for almost all deaths.

Furthermore, recognizing APL as a medical emergency that requires specific and simultaneous actions, including rapid and aggressive supportive care for bleeding and coagulopathy, early diagnosis with new molecular techniques, such as anti-PML mAb, prompt initiation of ATRA, transferal of patients to experienced medical centers when the disease is first suspected and the identification of high-risk patients to optimize treatment are key measures in improving the outcomes.

In conclusion, the present study demonstrates the reality of APL in the 20th century in a developing country and a public university hospital. Our results have shown that the rapid laboratory diagnosis of patients and immediate initiation of treatment with ATRA directly influence their survival. However, some cases had hemorrhagic complications that may be associated with the difficulty of patients to access the hospital, difficulty in recognizing early symptoms and difficulty in advanced or blood support.

The presence of severe bleeding is still the most important impact factor for death and its early recognition at patient presentation is very important and might be a useful tool in the identification of high-risk patients. However, more studies, continuous networking programs and basic research in developing countries must continue to be performed.

The authors declare no conflicts of interest.