This retrospective cohort study included 222 patients receiving chemotherapy treatment at three tertiary SUS hospitals (Hospital Geral de Fortaleza, n = 112; Hospital Universitário Walter Cantídio, n = 79, and; Hospital Cesar Cals n = 31) in Ceará, a state in northeastern Brazil, between January 2013 and December 2020, with 5 years of post-diagnosis follow-up. The chemotherapy protocols were the same at the three centers. Originally, information was retrieved from 273 medical records, but 51 were excluded due to duplication (n = 3) or unavailable/incomplete archive/clinical data (n = 48). The inclusion criteria were: patients of both sexes aged 18 years or over, diagnosis of AML on bone marrow aspiration showing the presence of blasts in a count equal to or over 20% of the cells represented with characteristics of myeloblasts9 and positive membrane surface staining for clusters of differentiation on immunophenotyping performed in flow cytometry.10 Pediatric patients and patients with other hematological diseases were excluded. Additionally, patients with acute promyelocytic leukemia with PML:RARA fusion were not excluded.

The study protocol was approved by the national clinical research platform (Plataforma Brasil, CAAE 44087220.0.1001.5052) and by the institutional review board. Following approval, the medical records were made available for analysis from May to July 2021. Data were collected by completing a questionnaire using the Google Forms platform. All patients or their legal representatives gave their written informed consent.

The hospitals participating in the study were requested to provide the medical records of patients diagnosed with the ICD codes C92, C92.0, C92.2, C92.4, C92.4, C92.5, C92.7 and C92.9. Information was collected on sex, date of birth, age at diagnosis and performance status at diagnosis according to the Eastern Cooperative Oncology Group (ECOG) performance scale (0 = fully active; 1 = restriction of physical activity, but able to work; 2 = able to perform self-care; 3 = limited self-care; 4 = completely unable, and; 5 = death).11

The presence of previous comorbidities was evaluated, including arterial hypertension (defined as systolic pressure ≥ 140 mmHg and/or diastolic pressure ≥ 90 mmHg), diabetes mellitus (defined as fasting blood glucose > 126 mg/dL or casual blood glucose ≥ 200 mg/dL), dyslipidemia (defined as LDL cholesterol ≥ 160 mg/dL or triglycerides ≥ 150 mg/dL or HDL ≤ 40 mg/dL in men and ≤ 50 mg/dL in women) and heart disease (defined as pre-chemotherapy echocardiography with an ejection fraction of ≤ 55%). The BMI was calculated by dividing weight (kg) by height (m) squared (overweight = BMI at 25 - 29.9 and obese = BMI ≥ 30).12

Information was also collected on smoking13 and alcohol14 consumption, family history of cancer (limited to first-degree relatives), previous radiotherapy or chemotherapy, personal history of hematologic diseases (myelodysplastic syndromes, chronic myeloid leukemia, chronic lymphocytic leukemia and myeloproliferative neoplasms) and occupational exposure. Non-melanoma skin cancer was not included.

The clinical history of the disease was recorded, starting with the initial symptoms (fever, weight loss, asthenia, hyporexia, bleeding, lymph node enlargement, hemorrhagic manifestations, infections and pain). The time from the onset of symptoms to diagnosis and from diagnosis to onset of treatment was documented, even for patients who died before initiating treatment. All diagnostic test results were recorded, including blood count, bone marrow aspiration, profile of immunophenotyping (according to the FAB classification: M0 = undifferentiated, M1 = minimal differentiation, M2 = poorly differentiated, M3 = promyelocytic, M4 = myelomonocytic, M5 = monocytic, M6 = erythrocytic, M7 = megakaryocytic and not applicable/not classified), karyotype with genetic alterations, categorized by risk (favorable, intermediate, unfavorable or high-risk) and molecular biology, when available.

Treatment response was evaluated, including remission after induction, refractoriness to chemotherapy, relapse during consolidations or after the end of the cycles, indication for and submission to bone marrow transplantation (BMT) (distinguishing between the presence and absence of compatible donors and whether they were evaluated) and the rescue schedule outcome. The main treatment regimen was the 7+3 protocol, or other options by azacitidine monotherapy, subcutaneous cytarabine or oral hydroxyurea as palliative therapy, the Pethema protocol15 and exclusive palliation.

The clinical outcome was documented, with the assessment of the disease status (disease in remission, active or cured) five years after diagnosis in patients without relapse. In addition, the presence or absence of relapse (including after BMT) and the time between the first remission and the first relapse were registered. Periodic blood count evaluations were performed and, if any change was observed, such as the presence of blasts, leukocytosis or cytopenias, the myelogram was used to document disease activity. Lab tests were performed 6 months, 1 year, 2 years and 5 years after diagnosis to identify the main causes of death (e.g., loss of response to treatment, infections, bleeding, chemotherapy toxicity, acute myocardial infarction and stroke).

For the purpose of statistical analysis, clinical and demographic parameters were expressed as mean values ± standard deviation (continuous variables) or as frequencies and percentages (categorical variables). Median values and ranges were calculated for non-normally distributed continuous variables. Kaplan-Meier charts were used to show patient survival at 6 months, 1 year, 2 years and 5 years. The level of statistical significance was set at 5% (p < 0.05). All analyses were performed using the software IBM SPSS Statistics (IBM Corp., Armonk, NY, USA).

The female sex was slightly prevalent (56.5%) in our cohort of 222 patients. The mean age at diagnosis was 44.1 ± 16 years (range: 18 - 87). As for clinical status, most patients (60%) were classified on the ECOG scale as 0, while 17% were classified as 1 and 16.1%, as 2 (patients capable of going to an appointment alone). The minority (6.7%) were completely incapable. Many were overweight (36.0%) or obese (16.2%). Other comorbidities are shown in Table 1.

The most prevalent symptom was asthenia/adynamia (69.1%), followed by fever (51.9%), pain (39.8%), hemorrhagic manifestations such as petechiae, ecchymosis and bleeding from the gastrointestinal tract (46.5%) and dyspnea (24.5%). The mean values of the initial blood count were: hemoglobin 7.4 g/dL ± 2.1, white blood cells 41.245 ± 80.321/mm3 (of which 34.2 ± 32.2% were leukemic blast cells) and platelets 66.970 ± 84.101/mm3. Blasts accounted for 64% (median) on bone marrow aspiration. Almost all patients (94.1%; n = 209) had access to immunophenotyping by flow cytometry, but 20% (n = 44) did not have access to karyotyping, which is essential for cytogenetic risk stratification.

Karyotyping was performed for 177 patients, 22 of whom were without metaphase growth. The 155 cytogenetic results were divided into favorable (34.19%; n = 53), intermediate (52.25%; n = 81) and unfavorable (13.54%; n = 21) prognoses. The abnormality t(15;17) was observed in 14.4% (n = 27) and 34.2% (n = 53) normal karyotypes in patients with favorable and intermediate risk, respectively. Half of the patients (n = 111) had access to advanced molecular biology tests: PML-RARA fusion gene tests (n = 61), FLT3 mutation searches (n = 42), BCR-ABL (n = 27) and NPM1 (n = 20). Some patients had access to more than one type of test. Based on the results of the molecular biology tests, the patients were classified according to the WHO criteria into good (42.4%; n = 76), intermediate (41.9%; n = 75) and unfavorable (15.6%; n = 28) prognoses.

The mean time between the onset of symptoms and the diagnosis was 55.2 ± 65.3 days (median 30; range: 1 - 365). A few patients (4.9%; n = 11) died before initiating treatment, with a mean interval of 16 ± 22.7 days between the diagnosis and the onset of chemotherapy. After the induction protocol, 145 (68.7%) patients went into remission, 66 (29.7%) were refractory to treatment and 11 (4.95%) died. Despite being in remission at the time of the analysis, 29.7% (n = 66) were refractory to induction or relapsed and required rescue therapy at some point during the treatment. The BMT (considered a curative therapy) was performed in 34 individuals (15.3%). All patients were referred for BMT after the first remission.

The 5-year median overall survival was 38.82 months (95%CI = 35.47 - 42.17). Furthermore, in 5 years, the overall survival rate was 39.4%; in 2 years it was 56.5%; 66.5% in one year, and; 74.9% in six months of follow-up. (Figure 1). No significant difference in survival was observed between the sexes (p = 0.3020), with 51.2% of women and 63% of men alive at 5 years. Eligibility for BMT was 40.2% for younger patients (< 65 years) and 27.03% for older patients (≥ 65 years) (Figure 2).

Figure 1..

Overall survival rate of patients with acute myeloid leukemia, stratified into 6 months, 1 year, 2 years and 5 years of follow-up. (“P-value” should have a hyphen in it).

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Figure 2..

Overall survival among younger (< 65 years) and older patients (≥ 65 years) with acute myeloid leukemia. (P-value” should have a hyphen in it).

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The median overall survival was 38.8 months.

The overall survival differed significantly according to the risk, as determined by cytogenetic testing (p = 0.003), with 46.11% survival of patients classified as favorable, 37.70% of patients classified as intermediate and 37.75% of patients classified as unfavorable. When patients with acute promyelocytic leukemia (APL) were excluded from the statistic, the values were 42.05% (favorable), 38.07% (intermediate) and 40.43% (unfavorable), with no significant difference (p = 0.216) (Figure 3).

Figure 3..

Survival of patients classified on cytogenetic testing as favorable, intermediate and unfavorable prognoses. (a) acute promyelocytic leukemia included in the cohort. (b) acute promyelocytic leukemia excluded from the cohort.

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Despite being in remission at the time of the analysis, 66 (29.7%) were refractory to induction or relapsed and required salvage therapy at some point during treatment. The initial response to the first cycle of chemotherapy had a positive effect on the final survival (59.10% who did not go into remission after induction died within 5 years). The main causes of death were progression of the underlying disease (37.72%), bacterial infections (32.58%), hemorrhage (8.80%) and thrombotic events, such as heart attack and strokes (5.36%) (Figure 4). For these patients, the time from diagnosis to death was 11.3 months, with a median of 6 months of treatment.

Figure 4..

Statistical distribution of the main causes of mortality in our cohort of patients with acute myeloid leukemia.

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