Acute Lymphoblastic Leukemia (ALL) is a lymphoid-cell hematological neoplasm.¹ It is the tenth leading cause of cancer mortality worldwide, and responsible for 8.5% of deaths in Latin America² and for 1,610 deaths in Colombia from 2007 to 2011.³ Despite the mortality and complications are higher in the adult population than in the pediatric one,^4,5 the investigation about ALL is especially focused on children due to its incidence.^6,7 This implies the research in adults is scarce; consequently, there is a lack of information about the complications of the disease and the ones related to chemotherapeutic treatment in the Colombian adult population suffering from this entity.³

Since the chemotherapeutic treatment and the disease by itself cause unpleasant adverse events for the patient^6,7, describing the complications (tumor lysis syndrome, febrile neutropenia, sepsis), cause of intensive care unit (ICU) admission, outcomes, and death cause in adult patients diagnosed with ALL could improve care and a better quality of life which, in turn, may reduce mortality of this group of patients. For this reason, the objective of this study is describing the chemotherapeutic treatment complications developed in adult Colombian patients diagnosed with ALL admitted to Hospital San Rafael in Bogotá, Colombia.

Study design

A cross-sectional study was made. It included patients admitted to Hospital San Rafael in Bogotá, Colombia (between August 1^st, 2016 and August 31^st, 2017) and diagnosed with ALL. The data were collected from clinical records of patients registered in its hematology group database.

Population

Female and male subjects were included, they were 18 years or older with a confirmed diagnosis of ALL by bone marrow biposy containing at least 20% of blast cells and immunohistochemical analysis. The molecular analysis (Philadelphia chromosome status) was not depicted within the variables. The sampling method was non-probabilistic, involving all the patients admitted to the hospital during a 13-month period. Exclusion criteria were: incomplete clinical record, death before having an immunohistochemical diagnosis, and patients who did not develop any complications at the time of admission and during the hospital stay.

Measurements

The measures were taken from the clinical records. The demographic variables included were sex and age. Additionally, all the variables related to diagnosis and subtype of ALL by immunohistochemistry, initiation of a chemotherapeutic regimen, the specific regimen, and treatment phase were also described. The mean complications described in this group of patients were febrile neutropenia (with its suspected infectious foci), tumor lysis syndrome, and cytopenia (other than neutropenia). Other complications were infectious processes by sepsis (defined by SEPSIS III criteria).

When outcomes were observed, we focused on the cause for ICU admission, vital status at the end of the study, and a fatal outcome (if reported); the cause of death was also described.

Statistical analysis

Percentages and frequencies were used to describe qualitative variables. Statistical mean, standard deviation (SD), median, and extreme values were applied to those variables. Individuals diagnosed with ALL and the complications they presented during their hospitalization were analyzed. Patients were classified by ALL subtype and complications. The statistical analysis was made using SPSS software (21^st version) with a license acquired by Universidad El Bosque.

The Research Ethics Committee from Hospital Universitario Clínica San Rafael approved the study during the August 30^th, 2017 session, on the basis that the development of the trial would observe the principles established in the Declaration of Helsinki and the guidelines of Resolution 8430 of the Colombian Ministry of Health in 1993. It granted the approval on the condition of guaranteeing the security and confidentiality of the information provided to the investigators, and assuming the benefits for the academic and clinical domains. All the authors of the study attest this condition was met.

A total of 116 patients with hematological neoplasms were admitted to Hospital San Rafael between August 1^st, 2016 and August 31^st, 2017. Twenty-four of them had a diagnosis of ALL with an equal proportion of sexes and an average age of 34.08 years (SD 15.3) (table 1).

Four patients (16.7%) presented compromised Central Nervous System (CNS) by a blast-cell tumor on cerebrospinal fluid, identified when a lumbar puncture and a flow cytometry were performed (table 1).

From the 24 patients with ALL, twenty-one (87.5%) patients received a chemotherapeutic regimen. Three patients did not receive it: two of them rejected the treatment; the other did not receive it because there was a consensus among the patient, his family, and the treating physicians to start palliative treatment in an outpatient context. The chemotherapeutic regimen was described with a distribution of ten patients receiving GRAAL-2003 (41.7%) and other four treatments. A secondary description of the treatment phase was made with nineteen cases (86.4%) receiving induction treatment (table 1).

The population was divided by ALL subtype (defined by immunophenotyping) as Pre- B cell ALL with nineteen cases (79.1%), followed by early-T cell ALL with two cases (8.3%). Less common subtypes were combined: early pre-B cell ALL and mature B-cell with two cases (8.3%) (table 1).

The complications presented in patients with ALL during the study were febrile neutropenia in 87.5% of patients; defined as core temperature over 38.3 degrees Celsius in a patient with an absolute neutrophil count less than 500 cells, tumor lysis syndrome in 37.5%, in which the criteria of hyperkalemia, hypocalcemia, hyperuricemia, and hyperphosphatemia were all considered for diagnosis. Concomitant anemia, and thrombocytopenia accounting for 70.8%, infection complicated by sepsis in 33%, and admission to ICU in 20.8% of patients (table 2).

The mean time to develop febrile neutropenia was 18.2 days (SD 20.9). Fourteen (58.3%) patients with febrile neutropenia had a suspicious or confirmed infectious focus. Bloodborne (28.6%) and respiratory tract infections (21.4%) were the two most common infectious foci described in patients with this complication (table 2).

Staphylococcus epidermidis and Klebsiella pneumoniae were the most frequent bacterial causative agents isolated in eight patients (33.3%), accounting for 50% of the cases. It is worth noting that there was one pregnant patient diagnosed with febrile neutropenia and urinary tract infection with two simultaneously isolated agents in her urine culture (Enterobacter cloacae and Klebsiella pneumoniae) (table 2).

There were three causes for admission to ICU: septic shock (50%), a risk of respiratory failure secondary to neurological impairment (25%), and febrile neutropenia in a pregnant patient (25%) (table 2).

Almost half of the patients included had a fatal outcome at the end of the study (45.8%). The most frequent cause of death was a septic shock (60%), followed by cardiac arrest (30%) and multiple organ failure (10%) with no infectious origin, suspected or demonstrated (table 2).

All the information provided in this study has significant value concerning the complications developed in patients diagnosed with hematological malignancies because of two main reasons. On the one hand, there is a lack of clinical reports describing the unique characteristics and behavior of the complications in adult Colombian patients with ALL. Thus, additional clinical data may be of great significance for patient outcomes and for the development of future studies. On the other, it is the first study known to date describing the complications in patients with ALL at Hospital San Rafael and it is, foremost, the first study notable to date in Colombia.

Most of them were the result of febrile neutropenia, with at least one infectious focus suspected in the clinical records. From those infectious foci, bloodborne and respiratory tract infections were the most common, specifically by Klebsiella pneumoniae and Staphylococcus epidermidis. In some of the patients (n=8) with an infectious complication, sepsis was present as a subsequent event. It is noteworthy that septic shock was the cause of ICU admissions in 50% of the patients. Tumor lysis syndrome and anemia/thrombocytopenia were other complications described.

One of the major findings in our results was the high frequency of febrile neutropenia and infectious complications that in a significant number of cases were associated with unfavorable outcomes, such as multiple organ failure and death. Therefore, the clinicians should always have these complications in mind when a patient with hematological malignancies is receiving or is about to start a chemotherapeutic regimen.

Our results are consistent with the findings described in the study of Enciso et al.: most of the patients were men (62.5%), and the most common subtype of ALL was the Pre-B cell immunophenotyping. However, the chemotherapeutic regimen mostly used in Enciso et al. was Hyper-CVAD.⁸ In a Mexican Study about infectious complications in ALL, Hyper-CVAD was also the most common regimen⁹; GRAAL 2003 was the most frequent scheme used in our patients. Despite the fact that we did mention the type of chemotherapeutic regimen, there was not a specific regimen dose inside of the clinical records of each patient in the study.

The infectious complications present in neutropenic patients are well described in the medical literature^10-13, and our findings are also consistent with other studies, whose first cause of death is an infection complicated by sepsis, just like the findings in Nachman et al., where approximately 66% of deaths were the result of sepsis.^14,15 Furthermore, the most common cause of infection in our study was bloodborne-related, which is an important finding to promote and to develop future studies about the predisposing factors in bloodborne infections of patients diagnosed with ALL.

In an Australian study carried out by Dix et.al, the reported infection incidence was 21%. When an infectious focus was confirmed, the first cause was bloodborne-related.¹⁶ In a Mexican retrospective observational study, the first cause of infection was pneumonia in 47 out of 70 patients.⁹ This difference might be explained by the fact that in the aforementioned study, other types of leukemias different from ALL were included and many of those patients did not receive intensive chemotherapy scheme.

Since this is a descriptive study, a clear relationship between the presence of specific risk and the development of certain disease or complication cannot be established. Neither is it possible to provide homogeneous information about demographics, occupation or nutritional data of the patients. Likewise, as an observational study involving one center, with a relatively small population, it can be considered as the starting point to develop new studies focused on the early detection of complications related to this group of patients. One strategy proposed by the authors is to include other centers to collect a larger population with this disease.