ARTÍCULO DE REVISIÓN

 

Clinical and epidemiological aspects of leukemias

 

Aspectos clínicos y epidemiológicos de las leucemias

 

 

Anne Louise Soares Almeida, Isabelle Campos de Azevedo, Diana Paula de Souza Rego Pinto Carvalho, Allyne Fortes Vitor. Viviane Euzébia Pereira Santos, Marcos Antonio Ferreira Jr

Department of Nursing, Health Science Center, Federal University of Rio Grande do Norte, Natal/RN, Brazil.

 

 

---

ABSTRACT

Leukemia is a group of clonal diseases derived from a single cell with a genetic alteration in bone marrow or peripheral lymphoid tissue, and each type is determined by the specificity of the source cell. The objective of this research was to synthesize studies that characterize the clinical and epidemiological profile of patients with leukemia, the types of treatments used, duration and outcomes for the cases. This study is an integrative review of literature through databases Medical Literature Analysis and Retrieval System Online (MEDLINE), SCOPUS, Cumulative Index to Nursing & Allied Health Literature (CINAHL) and Science Direct. There were 4,274 articles rescued in the initial search, 188 were selected to compose the review sample after applying all the criteria for inclusion and exclusion adopted. Full articles were grouped into four categories, according to the variables of research: (a) more frequent subtypes of leukemia; (b) most widely used treatment; (c) duration of treatment; and (d) endpoint of the cases. It is concluded a prevalence of leukemia in pediatric patients, with a predominance of the subtype Acute Lymphoblastic Leukemia (ALL). In general, the male population is more affected by hematological malignancies. As the therapy is used, each leukemia subtype had its peculiarities regarding the treatment, especially the introduction of imatinib for chronic myeloid leukemia (CML) and prophylactic cranial irradiation for cases of ALL. Chronic leukemia showed higher treatment duration. There was a significant improvement in survival of Acute Myeloid Leukemia, Chronic Lymphoid leukemia, CML and ALL, the latter approximately with 90% cure rate in children.

Keywords: leukemia; lymphoma; epidemiology; hematologic neoplasms; multiple myeloma; prognosis; drug therapy.

---

RESUMEN

La leucemia es un grupo de enfermedades clonales derivadas de una única célula con una alteración genética en la médula ósea o tejido linfoide periférico, y cada tipo se determina por la especificidad de la célula de origen. El objetivo de esta investigación fue sintetizar los estudios que caracterizan el perfil clínico y epidemiológico de los pacientes con leucemia, los tipos de tratamientos usados, la duración y los resultados para los casos. Este estudio es una revisión integradora de la literatura a través de bases de datos de análisis médicos, literatura y recuperación de sistema en línea (MEDLINE), SCOPUS, Cumulative Index de Enfermería y Salud Aliada Literatura (CINAHL) y Science Direct. Había 4 274 artículos rescatados en la búsqueda inicial, se seleccionaron 188 para componer la muestra de revisión después de aplicar todos los criterios de inclusión y exclusión adoptada. Los artículos completos se agruparon en cuatro categorías, según las variables de investigación: (a) los subtipos más frecuentes de leucemia; (b) el tratamiento más utilizado; (c) la duración del tratamiento; y (d) el punto final de los casos. Se concluye una prevalencia de leucemia en pacientes pediátricos, con predominio del subtipo de leucemia linfoblástica aguda (LLA). En general, la población masculina se ve más afectada por neoplasias hematológicas. Como se utiliza la terapia, cada subtipo de leucemia tenía sus peculiaridades con respecto al tratamiento, especialmente la introducción de imatinib para la leucemia mieloide crónica (CML) y la irradiación craneal profiláctica para los casos de ALL. La leucemia crónica mostró una mayor duración del tratamiento. Hubo una mejora significativa en la supervivencia de la leucemia mieloide aguda, leucemia linfoide crónica, LMC y LLA, aproximadamente, este último con la tasa de curación del 90% en los niños.

Palabras clave : leucemia; linfoma; epidemiología; neoplasias hematológicas; mieloma múltiple; pronóstico; quimioterapia.

---

 

INTRODUCTION

The World Health Organization (WHO), through the World Cancer Report 2014 characterizes cancer as a public health problem, especially among developing countries, expecting that the impact of cancer in the population in coming decades corresponds to 80% on more than 20 million new cases estimated for 2025¹.

For Brazil, there is an estimated of 600 000 new cases of cancer in 2016 ². Among the cancers that affect the general population, leukemia has events from childhood to the elderly stages. There were 352 000 new cases of leukemia estimated worldwide in 2012, corresponding to 2.5% of all new cancer cases and 265 000 deaths in the same period worldwide¹. Leukemia is responsible for approximately 3% of all cancer cases in Brazil and worldwide³.

Leukemia is a group of clonal diseases derived from a single cell with a genetic alteration in bone marrow or peripheral lymphoid tissue, with their types determined by the source cell specification, by cytologic examination, immunohistochemistry and cytogenetic classified as acute myeloid leukemia (AML), chronic myeloid leukemia (CML), acute lymphoblastic leukemia (ALL) and chronic lymphoid leukemia (CLL)⁴.

The AML diagnosis is determined by the uncontrolled growth of differentiated cells of the myeloid type in the blood or bone marrow characterized by the presence of more than 20% blasts and represents 90% of cases of leukemia in adults. CML is a clonal disorder of a pluripotent stem cell, called as Philadelphia chromosome (Ph) when translocation occurs from the long arm of chromosome 22 to 9 and 9 to 22. This translocation brings most of the ABL to gene BCR region of chromosome 22, responsible for 15% of diagnoses of leukemia⁵.

The ALL is characterized by immature lymphoid cells accumulate in bone marrow and is the most prevalent hematologic malignant neoplasm of childhood, with a higher incidence of two and five years old, and it is 25% of all cancers in this age group. CLL is diagnosed from the accumulation of mature lymphocytes of type B and T blood. However, it does not interfere with the production of normal cells, as in the previous type⁶.

Given the importance of this issue and the social impact generated by the diagnosis and treatment of this disease, this study aims to summarize the studies that characterize the clinical and epidemiological profile of patients with leukemia, the type of treatment used, duration and outcomes for the cases.

 

METHOD

This study is an integrative literature review, to conferring scientific criticality followed the following steps: a) identifying the problem or research question, b) search the databases, c) evaluation of the data, d) data analysis, e) presentation of the results⁷.

For the execution of searches of electronic databases, the following research question has been defined among the leukemia subtypes, which is the most common, the most common treatment, duration and outcomes found?

The literature search took place between December 2015 and January 2016, using the proxy licensed by the Federal University of Rio Grande do Norte (www.capes.ufrn.br/porta3128) by the following databases: Medical Literature Analysis and Retrieval System Online (MEDLINE), SCOPUS, Cumulative Index to Nursing & Allied Health Literature (CINAHL) and Science Direct.

The crosses were used by the indexed descriptors of Medical Subject Headings (MeSH): 1# "leukemia", 2# "epidemiology', 3# "hematologic neoplasms" and 4# "prognosis". The crosses were performed using the Boolean AND operator: 1# AND 2#, 1# AND 2# AND 3#, 1# AND 2# AND 4# and 1# AND 2# AND 3# AND 4#. Uncontrolled search was performed only in Science Direct base to obtain a representative sample of published articles that met the inclusion criteria. It was not used time frame, thus all the items available were analyzed.

The selected studies met the following inclusion criteria: studies addressing the clinical and epidemiological characteristics of patients with leukemia by the prevalence of characteristics, treatment, and outcome. Articles that were not available in full on the selected databases, studies of literature review type, reflective articles, previous notes, letters to the editor, pilot studies and qualitative research were excluded, as well as those who did not answer the main question of this study.

The first selection of studies was carried out by reading the titles and abstracts, with emphasis on objectives and results. Data were separated by the database and relevant topics. For data extraction, the classification of items according to the information presented was carried out: prevalence, treatment, outcome, incidence and treatment, incidence and outcomes, treatment and outcome and incidence/treatment/outcome.

In an initial search, there were 4 274 articles rescued, 188 of them were selected for the sample of this review after application of the inclusion criteria. Of the 4 086 studies excluded, 3 970 addressed the topic, but not on the topics of interest to this review, 28 articles were duplicated, 61 were literature review articles, and 27 had scientific events.

 

RESULTS AND DISCUSSION

Table 1 shows the 188 selected articles, organized by a database that was recovered and approached themes. There were 62 studies on the prevalence of the disease, 7 addressing kinds of treatments, 53 addressing the outcomes, seven on the prevalence/treatment/outcomes, three prevalence/treatment, 33 on the prevalence and outcomes and 23 addressing the treatments and their outcomes.

Table 2 is the distribution of the final sample articles per database and performed by crossing, with a majority of SCOPUS articles and by #1 combinations (leukemia AND epidemiology).

Because it was not a time frame determined, there was a significant distribution of studies by year of publication, giving an extensive analysis of the productions on leukemia over time. Studies published between 1964 and 2015 were rescued, of which 135 articles were published in the last ten years. Therefore, it is clear an important increase of publications in the last decade.

After systematic reading, the complete articles were grouped into four categories according to the variables of research: (a) more frequent subtypes of leukemia; (b) most widely used treatment; (c) duration of treatment; and (d) outcomes of the cases.

More frequent subtypes of leukemias

Most studies on this topic reported childhood leukemia, and the most incident subtype is the ALL⁸. Leukemia is approximately one-third of cancer cases in children aged 0 to 14 years old and 10% of adolescents aged 15 to 19 years old. In Europe, the overall incidence rate for leukemia in children was 44 per million people per year between 1988 and 1997. Among the types of leukemia, the lymphoid is found in 81% of cases, non-lymphocytic acute leukemia in 15%, CML in 1.5% and unspecified leukemia in 1,3% of cases⁹.

In Brazil, it is estimated the occurrence of 10 070 new cases of leukemia in 2016, with male prevalence (5 540 cases) compared to women (4 530 cases). This type of cancer is the sixth most common in men in the northern region of the country, with an incidence of 3,81 cases per 100 thousand inhabitants².

In a survey conducted in a city in Brazil´s southeastern region in the 1990s, it was found an overall incidence of ALL of 12,5 cases per million people per year¹⁰. In three state capitals, two of them located in the northeast and one in the southeast, the estimated incidence was 5,76; 6,32 and 5,48 cases per 100,000 inhabitants, respectively. Despite the high underreporting of childhood cancer, ALL incidence rates in children are similar to those of developed countries¹¹.

Between 1979 and 1989 in Kuwait, the ALL was the most frequent among 723 cases (44.2%), with prevalence in the group aged between 0-4 years old, and the most common leukemia was in the children (90,5%). The AML represented 32,4% of leukemia and showed a progressive increase in incidence with age. On the other hand, CML constituted 14,8%, and CLL was 8,6% of all cases ¹².

In Cape Province, South Africa, of the 460 cases acute leukaemia diagnosed, 223 (48,5%) occurred in white patients and 237 (51,5%) in those of mixed ancestry. The relationship between the incidence of acute leukemia and ethnicity was 2,12, 1,37 and 0,58 per 100 000 people white, brown and black, respectively. The average age of white people was 30 years old and for brown people, it was 15 years old, comparable data to black patients being 16 years old¹³.

Another point of the overall analysis of the incidence of hematological malignancies found that with increasing age there was a decrease of lymphoid neoplasms^12,14. Nevertheless, some studies have highlighted the increasing number of cases of CLL among women 50-64 years old and attributed the phenomenon to the introduction of breast cancer screening, which resulted in a large group of women under greater surveillance that possibly has led to increased detection of this type of leukemia¹⁵.

In Canada, age-specific prevalence rates showed a steady increase with advancing years for this disease, being more common in men than in women (1,80:1)¹⁶. In the United States, CLL is the most common form of leukemia in adults. Among 1992 and 2007, there were 30 622 cases, of which men stood out with a higher incidence than women¹⁷.

In France, the incidence rate of AML remained stable over time, ranging from 2,5 to 3,5 cases per 100 000 people per year. The average age at diagnosis was 63 years old. The ALL had an incidence of 1.5 cases per 100 000 in habitants/year, and it was more frequent in children aged four to six years old. The B-cell ALL were more common than T-cell ALL but showed better prognosis¹⁸.

Biphenotypic leukemia, a rare condition, also had its impact on the US database of the Surveillance, Epidemiology, and End Results Program (SEER), between 2001 and 2011, which identified 313 patients with mixed phenotype acute leukemia. It presented an incidence of 0,35 cases per million people per year, with the worst result of prognosis among all subtypes of leukemia, and a direct relationship with age, extremely unfavorable for elderly patients¹⁹.

The hairy cell leukemia (HCL) is also an unusual and barely frequent hematologic tumor subtype. In Mexico, the disease is about 1,12% of all cases of leukemia²⁰. In Israel, the national database recorded 147 cases of HCL among men and 34 for women in the period 1991-2001, with incidence rates adjusted for age of 1,62 cases per million women and 7,97 per million people per year²¹.

Globally, for AML and ALL subtypes, according to the French-American-British (FAB) classification, it was found that the incidence of AML-M2 was higher than the AML-M1. For ALL, there was a predominance of ALL-L2 subtype²². According to the Health World Organization classification criteria (WHO) B cell ALL consisted of the most common subtype¹⁰.

Most used treatment

Each leukemia subtype showed their peculiarities relating to treatment. For AML, a minority of patients held the Hematopoietic Stem Cell Transplantation (HSCT). However, this procedure consists of a treatment modality used more frequently for oncology-hematological diseases genetically inherited or acquired²³.

The HSCT can occur through autologous transplantation, when the progenitor hematopoietic cells (PHC) are from the patient; allogeneic when PHC are from donors with compatible Human Leukocyte Antigen (HLA), related when they are from the same family and not unrelated without a consanguineous donor; or syngeneic transplant, when PHC are identical twins²⁴. After the graft, cyclosporine and mycophenolate mofetil are commonly found, preceded by total body radiation in D0 with or without the use of fludarabine²⁵.

The intravenous busulfan consisted of another drug used for autologous HSCT process in patients with AML. It has low toxicity compared with the version administered orally, easy to administer and associated with lower rates of the sinusoidal obstructive syndrome²⁶.

In the acute promyelocytic leukemia, characterized by the gene rearrangement involving the alpha retinoic acid receptor on chromosome 15, the treatment was through the administration of all-trans retinoic acid (ATRA) combined with based chemotherapy in anthracycline²⁷. The arsenic trioxide (ATO) is also an antineoplastic chemotherapeutic agent approved for the treatment of relapsed or refractory acute promyelocytic leukemia^{28, 29}. The ATO was used in preclinical studies for treating multiple myeloma, and the results showed a reduction in disease progression and induction of apoptosis in many cell lines that can be achieved safely in patients with this disease diagnóstido ^30-32.

For CML, the first-line treatment was continuously carried out using the kinase inhibitor mesylate tyrosine imatinib or in the second line, dasatinib, and nilotinib³³. Chronic lymphocytic leukemia (CLL) presented treatment centered on the use of fludarabine and cyclophosphamide and associated or not and with the cycle of one to five days, repeated every 28 days for up to six cycles. Its combined use was associated with a higher complete remission rate³⁴. Besides fludarabine, the chlorambucil was also used as a first line treatment³⁵.

In Germany, the most commonly used first-line regimens adopted bendamustine in combination with rituximab, fludarabine-associated with cyclophosphamide and rituximab and bendamustine alone. In the second-line treatment, they were very similar to the first and their choice was due to the pathophysiologic characteristics of each patient. Chlorambucil has been used in the treatment of two lines, but in a limited number of patients ³⁶.

In the cases of hairy cell leukemia, the pentostatin, and cladribine represented antineoplastic agents of choice for treatment, when pentostatin demonstrated an association between improving the health status of patients treated with minimal cost increase³⁷.

In ALL, the type of treatment varies between the combination of intrathecal methotrexate and adriamycin, and between radiation and cranial radiotherapy extended field for radiation³⁸. In a study conducted in Poland, patients received prednisone, vincristine, adriamycin and cyclophosphamide as a treatment for induction of remission. For consolidation, cytarabine and 6-thioguanine were administered and prophylaxis for Central Nervous System (CNS), patients, received cranial irradiation, intrathecal methotrexate, cytarabine and hydrocortisone³⁹. Prophylactic cranial irradiation composed the standard treatment in children who were at high risk of relapse into the CNS by residual leukemic cells⁴⁰. In the UK, the antineoplastic agent of choice for the ALL found was daunorubicin administered by peripheral venous access because of their high risk of venous thromboembolism⁴¹.

Duration of treatment

The duration of antineoplastic treatment ranged according to the therapy used and leukemia subtype. In CML, the median duration of therapy using the tyrosine kinase inhibitor of the first line (imatinib) was 39,8 months and the use of tyrosine kinase inhibitors in the second line (Dasatinib or Nilotinib) was 22,4 months³³.

CLL showed decreasing numbers of patients within six months after diagnosis with the early-stage disease since international guidelines have a stronger tendency to discourage the treatment of indolent patients without active disease¹⁵. The cycles of chemotherapy fludarabine and cyclophosphamide, associated or not, were repeated every 28 days for a maximum of six cycles³⁴. According to the National Cancer Institute Working Group, the average treatment duration was 9,2 years compared to 6,5 years updated by the International Workshop criteria and guidelines, which varies according to the monocyte count^42,43.

In the treatment of AML by chemotherapy, patients who achieved complete remission received a single course of Cytarabine 1,5 g/m² every one hour for 12 hours, which resulted in a total of 12 doses, for about four weeks after the record of complete remission. In some cases, intravenous mitoxantrone 12 mg/m² was used as a rescue therapy on days 7, 8 and 9, respectively⁴⁴.

For the cases of ALL, the treatment of remission induction, consolidation therapy phase, and maintenance, plus prophylaxis of central nervous system, showed an average total duration of 2,5 years³⁹.

Outcomes of cases

In general, the survival rate of patients with AML showed an increase significantly in recent years^9,45. This better prognosis can be associated with increased investments of hospitalization and chemotherapy. In a study from data collected in the SEER, it was found that a total of 34 subjects diagnosed with ALL, the median survival, was 2,4 months with less than 7% of patients alive at two years, and it was still observed that the higher, the younger were the chances of survival⁴⁶. In childhood, patients diagnosed between 10 and 19 years old are at increased risk of death compared to those diagnosed before 10 years, when the subtypes of AML with t (9;11) (p22;q23) MLLT3-MLL, AML without maturation and acute myelomonocytic leukemia showed indicative of poor prognosis ⁴⁷.

The same was observed for the survival rate in CML, mainly associated with the implementation of imatinib mesylate as first-line therapy ^33,48. In the period 1993-2008, in the United States and Japan, it was found that the age-standardized mortality rates declined significantly in both countries after the availability of imatinib ⁴⁸. The increase in spending on anticancer treatment was also associated with increased survival of patients with CML⁴⁹.

The combination of fludarabine with cyclophosphamide led to a significant increase in complete remission for CLL, a higher overall response and overall progression-free survival³⁴. Nevertheless, the B cells CLL has highly heterogeneous clinical course, and the prognosis is difficult to predict. In Gijón, Spain, in the 1997-2007 period, survival rates for intervals of five to ten years accounted for 87% and 73% for low risk, 75% and 49% for intermediate risk and 29% and 16% for high-risk, respectively⁵⁰. Survival expectations for long-term patients with CLL showed substantial improvements in the last two decades, except for patients 80 years old or older at diagnosis^{51, 52}. The main cause of mortality in patients suffering from this particular illness were infectious complications associated with low absolute monocyte count⁴³.

The more frequent ALL in childhood showed the relative five-year survival of approximately 90% of children with this diagnosis, and between 35 and 40% in adults in the same condition¹⁸. Despite treatment protocols include the prophylaxis of the central nervous system cranial irradiation, a relatively high incidence of relapse was observed in the CNS ³⁹. Thus, even if the ALL has high survival, this has evolved in such a way to present a risk of late effects in treated survivors, especially the risk of subsequent malignancy⁵³, such as the non-lymphoblastic leukemia, of myelodysplastic syndrome, osteoarthritis, fibroblast sarcoma, B cell ALL, lymphoma, thyroid carcinoma, basal cell carcinoma, adenocarcinoma, squamous cell carcinoma, meningioma, malignant histiocytosis anaplastic astrocytoma and glioblastoma. HSCT and high cumulative doses of cranial irradiation, etoposide, and cyclophosphamide are risk factors for this event⁵⁴.

Between 1943 and 2000, a total of 133 secondary malignancies were observed in 16 540 patients in a multicenter study in the American countries, Europe, Asia, and Oceania. Among them, 12 731 cases of leukemia, 1 246 Hodgkin's and 2 563 non-Hodgkin lymphomas, after a median follow-up period of 6,5 years. The most common secondary cancer after leukemia was brain cancer (19 cases), non-Hodgkin's lymphoma (nine cases) and thyroid cancer (nine cases)⁵⁵. In the Pediatric Research Hospital St. Jude in Memphis in the US, between 1962 and 1998 from 2 169 of ALL patients treated who achieved complete remission and had a median follow-up of 18,7 years, 123 of them developed secondary malignancies as the first event after acute lymphoid leukemia, 46 myeloid malignancies, three lymphomas, 14 basal cell carcinomas, 16 carcinomas, six sarcomas, 16 meningiomas and 22 brain tumors ⁵⁶.

For hairy cell leukemia (HCL), in the US, the median overall survival based on diagnostic period was five, six, four and 12 months for those diagnosed during 1973-1995, 1996-2000, 2001-2005 and 2006-2009, respectively. Thus, it was observed a recent sharp improvement in the survival of HCL, which can be associated with the use of improved therapeutic strategies ⁵⁵.

The results show a higher prevalence of leukemia in pediatric patients, especially the ALL subtype. However, this population is the highest percentage of healing, which can reach up to 90% of cases, which declines with advancing age. There was also that its impact is more pronounced in the white population. The AML is the second most common subtype of leukemia, and in general, the male population is more affected by hematological malignancies.

Regarding the therapy used, each leukemia subtype presented its particularities, highlighting the success of imatinib mesylate use for the treatment of CML. The prophylactic cranial irradiation is a complementary therapeutic method for the treatment of ALL, to prevent recurrence of the tumor in the central nervous system.

The anticancer treatment period varied according to the treatment employed and leukemia subtype. For chronic leukemias (CML and CLL) has been verified the longest period of treatment ranged from 22,4 months to 9,2 years, respectively.

In recent years, the mortality rates standardized by age decreased significantly for the cases of AML and CML. This prognosis improvement may be associated with increased investments with hospitalization and chemotherapy. For CLL, there was also an increased survival, but for patients over 80 years old. The main cause of mortality in patients suffering from this cancer is infectious complications associated with a low count of absolute monocyte. The ALL shows the relative survival of approximately 90% in children, but between 35 and 40% in adults. It is observed a recent sharp improvement in survival of HCL, which may be associated with the use of improved therapeutic strategies.

Even it has seen the intensification of studies related to the theme, this is a subject that needs to be constantly studied and updated its revised data and processed to generate information to encourage epidemiological data. Therefore, when tracing the epidemiological cancer profile, the reality of this disease in the society is exposed to which the study is directed, as is possible, from the results, the increased knowledge by the professionals regarding this disease and of the population affected by it.

 

ACKNOWLEDGMENT

To the Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq; scholarship) scientific initiation) and Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES; master's scholarship and PhD scholarship).

 

REFERENCES

1. Stewart BW, Wild CP. World Cancer Report 2014. Lyon (FR): IARC; 2014.

2. Instituto Nacional do Câncer. Coordenação de Prevenção e Vigilância. Estimativa 2016: incidência de câncer no Brasil. Rio de Janeiro: INCA; 2016.

3. Rêgo MAV, Fonseca AA. Mortality Trends from Leukemia in Salvador - Brazil, 1980 to 2012. Rev Bras Cancerol. 2015; 61(4):325-34.

4. Silva DS, Mattos IE, Teixeira LR. Mortality Trends from Leukemia and Lymphomas in People with less than 20 Years, Brazil. Rev Bras Cancerol. 2013;59(2):165-73.

5. Hoffbrand AV, Moss PAH. Fundamentos em hematologia. Porto Alegre: Artmed; 2013.

6. Cabral SNS, Santos SL, Beltrão AB, Augusto LGS. Baseline of acute lymphocytic leukemia for surveillance of environmental health on the oil refinery area of the State of Pernambuco, Brazil, 2004 to 2008. Epidemiol Serv Saúde. 2012 Dez;21(4):601-8.

7. Whittemore R, Knafl K. The integrative review: updated methodology. J Adv Nurs. 2005 Dec; 52(5):546-53.

8. Knox-Macaulay HHM, Brown LC. Descriptive epidemiology of de novo acute leukaemia in the Sultanate of Oman. Leuk Res. 2000 Jul;24(7):589-94.

9. Coebergh JW, Reedijk AM, Vries E, Martos C, Jakab Z, Steliarova-Foucher E, et al. Leukaemia incidence and survival in children and adolescents in Europe during 1978-1997. Report from the Automated Childhood Cancer Information System Project. Eur J Cancer. 2006 Sept;42(13):2019-36.

10. Rego EM, Garcia AB, Viana SR, Falcão RP. Characterization of acute lymphoblastic leukemia subtypes in Brazilian patients. Leuk Res. 1996 Apr;20(4):349-55.

11. Silva FA, Reis RS, Santos MO, Luiz RR, Oliveira MSP. Evaluation of childhood acute leukemia incidence and underreporting in Brazil by capture-recapture methodology. Cancer Epidemiol. 2009 Dec;33(6):403-5.

12. Al-Bahar S, Pandita R, Al-Muhannaha A, Al-Bahar E. The epidemiology of leukemia in Kuwait. Leuk Res. 1994 Apr;18(4):251-5.

13. Sayers GM, Rip MR, Jacobs P, Klopper JM, Karabus CD, Rosenstrauch WJ, et al. Epidemiology of acute leukaemia in the Cape Province of South Africa. Leuk Res. 1992 Oct;16(10):961-6.

14. Bekadja MA, Hamladjib RM, Belhani M, Ardjoun FZ, Abad MT, Touhami H, et al. A population-based study of the epidemiology and clinical features of adults with acute myeloid leukemia in Algeria: report on behalf of the Algerian Acute Leukemia Study Group. Hematol Oncol Stem Cell Ther. 2011;4(4):161-6.

15. Van den Broeka EC, Katerb AP, Van de Schans SAM, Karim-Kos HE, Janssen-Heijnen ML, Peters WG, et al. Chronic Lymphocytic Leukaemia in the Netherlands: Trends in incidence, treatment and survival, 1989-2008. Eur J Cancer. 2012 Apr;48(6):889-95.

16. Healeya R, Patela JL, Koninga L, Naugler C. Incidence of chronic lymphocytic leukemia and monoclonal B-cell lymphocytosis in Calgary, Alberta, Canada. Leuk Res. 2015 Apr;39(4):429-34.

17. Shenoy PJ, Malik N, Sinha R, Nooka A, Nastoupil LJ, Smith M, et al. Racial Differences in the Presentation and Outcomes of Chronic Lymphocytic Leukemia and Variants in the United States. Clin Lymphoma Myeloma Leuk. 2011 Dec;11(6):498-06.

18. Maynadiéa M, Troussard X. Épidémiologie des leucémies aiguës. RFL. 2015;2015(471);29-33.

19. Shi R, Munker R. Survival of patients with mixed phenotype acute leukemias: A large population-based study. Leuk Res. 2015 Jun;39(6):606-16.

20. Ruiz-Argüelles GJ, Cantú-Rodríguez OG, Gómez-Almaguer D, Cortés-Franco J, Góngora-Biachi RA, Pizzuto J et al. Hairy cell leukemia is infrequent in Mexico and has a geographic distribution. Am J Hematol. 1996 Aug;52(4):316-8.

21. Paltiel O, Adler B, Barchana M, Dann EJ. A population-based study of hairy cell leukemia in Israel. Eur J Haematol. 2006 Nov;77(5):372-7.

22. Nirina MOMH, Rakotoarivelo ZL, Ntoezara A, Rasolonjatovo AS, RakotoAlson AO, Rasamindrakotroka A. Epidemiology and diagnosis of acute leukemia in Ravoahangy Andrianavalona hospital Antananarivo Madagascar. African J Cancer. 2015;7:186-9.

23. Gangatharan SA, Grove CS, P'ng S, O'Reilly J, Joske D, Leahy MF, et al. Acute myeloid leukaemia in Western Australia 1991-2005: a retrospective population-based study of 898 patients regarding epidemiology, cytogenetics, treatment and outcome. Intern Med J. 2013 Aug;43(8):903-11.

24. Fermo VC, Radünz V, Rosa LM, Marinho MM. Profissionals' attitudes for patient safety culture in units of bone marrow transplantation. Rev Gaúcha Enferm. 2016;37(1):1-9.

25. Hegenbart U, Niederwieser D, Sandmaier BM, Maris MB, Shizuru JA, Greinix H et al. Treatment for acute myelogenous leukemia by low-dose, total-body, irradiation-based conditioning and hematopoietic cell transplantation from related and unrelated donors. J Clin Oncol. 2006 Jan;24(3):444-53.

26. Nagler A, Labopin M, Gorin NC, Ferrara F, Sanz MA, Wu D, et al. Intravenous busulfan for autologous stem cell transplantation in adult patients with acute myeloid leukemia: a survey of 952 patients on behalf of the acute leukemia working party of the european group for blood and marrow transplantation. Haematologica. 2014 Aug;99(8):1380-6.

27. Bassi SC, Rego EM. Molecular basis for the diagnosis and treatment of acute promyelocytic leucemia. Rev Bras Hematol Hemoter. 2012;34(2):134-9.

28. Niu C, Yan H, Yu T, Sun HP, Liu JX, Li XS, et al. Studies on treatment of acute promyelocytic leukemia with arsenic trioxide: remission induction, follow-up, and molecular monitoring in 11 newly diagnosed and 47 relapsed acute promyelocytic leukemia patients. Blood. 1999;94(10):3315-24.

29. Soignet SL, Frankel SR, Douer D, Tallman MS, Kantarjian H, Calleja E, et al. United States multicenter study of arsenic trioxide in relapsed acute promyelocytic leukemia. J Clin Oncol. 2001;19(18):3852-60.

30. Park WH, Seol JG, Kim ES, Hyun JM, Jung CW, Lee CC, et al. Arsenic trioxide-mediated growth inhibition in MC/CAR myeloma cells via cell cycle arrest in association with induction of cyclin-dependent kinase inhibitor, p21, and apoptosis. Cancer Res. 2000;60(11):3065-71.

31. Perkins C, Kim CN, Fang G, Bhalla KN . Arsenic induces apoptosis of multidrug-resistant human myeloid leukemia cells that express Bcr-Abl or overexpress MDR, MRP, Bcl-2, or Bcl-x(L). Blood. 2000;95(3):1014-22.

32. Hideshima T, Chauhan D, Richardson P, Mitsiades C, Mitsiades N, Hayashi T, et al. NF-kappa B as a therapeutic target in multiple myeloma. J Biol Chem. 2002;277(19):16639-47.

33. Henk HJ, Woloj M, Shapiro M, Whiteley J. Real-world analysis of tyrosine kinase inhibitor treatment patterns among patients with chronic myeloid leukemia in the United States. Clin Ther. 2015 Jan;37(1):124-33.

34. Flinn IW, Neuberg DS, Grever MR, Dewald GW, Bennett JM, Paietta EM et al. Phase III trial of fludarabine plus cyclophosphamide compared with fludarabine for patients with previously untreated chronic lymphocytic leukemia: US Intergroup Trial E2997. J Clin Oncol. 2007;25(7):793-8.

35. Panovská A, Doubek M, Brychtová Y, Mayer J. Chronic Lymphocytic Leukemia and Focusing on Epidemiology and Management in Everyday Hematologic Practice: Recent Data From the Czech Leukemia Study Group for Life (CELL). Clin Lymphoma Myeloma Leuk. 2010;10(4):297-300.

36. Knauf W, Abenhardt W, Dörfel S, Meyer D, Grugel R, Münz M, et al. Routine treatment of patients with chronic lymphocytic leukaemia by office-based haematologists in Germany-data from the Prospective Tumour Registry Lymphatic Neoplasms. Hematol Oncol. 2015 Mar;33(1):15-22.

37. Guest JF, Smith H, Sladkevicius E, Jackson G. Cost-effectiveness of pentostatin compared with cladribine in the management of hairy cell leukemia in the United Kingdom. Clin Ther. 2009;31:2398-415.

38. Haupt R, Novakovic B, Fears TR, Byrne J, Robinson LL, Tucker MA et al. Can protocol-specified doses of chemotherapy and radiotherapy be used as a measure of treatment actually received? A CCG/NIH study on long-term survivors of acute lymphocytic leucemia. J Clin Epidemiol. 1996 Jun;49(6):687-90.

39. Boguslawska-Jaworska J, Chybicka A, Koscielniak E, Armata J, Ochocka M, Koscielniak U et al. The results of high risk children's acute lymnphoblastic leukemia total therapy. A report from the polish children's leukemia/lymphoma study group. Europ Paediatr Hematol Oncol. 1984;1(1):107-12.

40. Pui CH, Campana D, Pei D, Bowman P, Sandlund JT, Kaste SC, et al. Treating childhood acute lymphoblastic leukemia without cranial irradiation. Engl J Med. 2009 Jun;360:2730-41.

41. Selwood K, Pizer B, Gibson B, Skinner R. Vascular access for daunorubicin during childhood acute lymphoblastic leukaemia induction treatment: A UKCCSG supportive care group and MRC childhood leukaemia working party survey. Eur J Oncol Nurs. 2008 Dec;12(5):476-8.

42. Call TG, Norman AD, Hanson CA, Achenbach SJ, Kay NE, Zent CS, et al. Incidence of chronic lymphocytic leukemia and high-count monoclonal B-cell lymphocytosis using the 2008 guidelines. Cancer 2014 Jul;120(13):2000-5.

43. Szerafin L, Jakó J, Riskó F. Prognostic value of absolute monocyte count in chronic lymphocytic leukaemia. Orvosi Hetilap. 2015 Apr;156(15):592-7.

44. Bow EJ, Gallant G, Williams GJ, Woloschuk D, Shore TB, Rubinger M, et al. Remission induction therapy of untreated acute myeloid leukemia using a non-cytarabine-containing regimen of idarubicin, etoposide, and carboplatin. Cancer. 1998;83(7):1344-54.

45. Shah BK, Ghimire KB. Improved survival among older acute myeloid leukemia patients - a population-based study. Acta Oncol. 2014 Jul;53(7): 935-8.

46. Lang K, Earle CC, Foster T, Dixon D, Van Gool R, Menzin J. Trends in the treatment of acute myeloid leukaemia in the elderly. Drugs Aging. 2005;22(11):943-55.

47. Hossain J, Xie L, Caywood EH. Prognostic factors of childhood and adolescent acute myeloid leukemia (AML) survival: Evidence from four decades of US population data. Cancer Epidemiol. 2015 Oct;39(5):720-6.

48. Chihara D, Ito H, Matsuda T, Katanoda K, Shibata A, Saika K, et al. Decreasing trend in mortality of chronic myelogenous leukemia patients after introduction of imatinib in Japan and the U.S. Oncologist. 2012;17(12):1547-50.

49. Menzin J, Lang K, Earle CC, Glendenning A. Treatment patterns, outcomes and costs among elderly patients with chronic myeloid leukaemia: a population-based analysis. Drugs Aging. 2004;21(11):737-46.

50. Rodríguez APG, García EG, Álvarez CF, Huerta AJG, Rodríguez SG. B-chronic lymphocytic leukemia: Epidemiological study and comparison of MDACC and GIMENA pronostic indexes. Med Clin. 2009 Jul;133(5):161-6.

51. Brenner H, Gondos A, Pulte D. Trends in long-term survival of patients with chronic lymphocytic leukemia from the 1980s to the early 21st century. Blood, 2008;111(10):4916-21.

52. Pulte D, Gondos A, Brenner H. Trends in 5- and 10-year survival after diagnosis with childhood hematologic malignancies in the United States, 1990-2004. J Natl Cancer Inst. 2008;100(18):1301-9.

53. Essig S, Li Q, Chen Y, Hitzler J, Leisenring W, Greenberg M, et al. Risk of late effects of treatment in children newly diagnosed with standard-risk acute lymphoblastic leukaemia: a report from the Childhood Cancer Survivor Study cohort. The Lancet Oncology. 2014 Jun;15(8): 841-51.

54. Borgmann A, Zinn C, Hartmann R, Herold R, Kaatsch P, Escherich G, et al. Secondary malignant neoplasms after intensive treatment of relapsed acute lymphoblastic leukaemia in childhood. Eur J Cancer. 2008 Jan;44(2):257-68.

55. Maule M, Scélo G, Pastore G, Brennan P, Hemminki K, Tracey E, et al. Risk of second malignant neoplasms after childhood leukemia and lymphoma: an international study. JNCI. 2007;99(10):790-800.

56. Hijiya N, Hudson MM, Lensing S, Zacher M, Onciu M, Behm FG, et al. Cumulative incidence of secondary neoplasms as a first event after childhood acute lymphoblastic leukemia. JAMA. 2007 Mar;297(11):1207-15.

57. Gonsalves WI, Rajkumar SV, Go RS, Dispenzieri A, Gupta V, Singh PP, et al. Trends in survival of patients with primary plasma cell leukemia: A population-based analysis. Blood. 2014 Aug;124(6):907-12.

 

 

Recibido: julio 26, 2016.
Aceptado: octubre 16, 2016.

 

 

Marcos Antonio Ferreira Jr . Universidade Federal do Rio Grande do Norte, Centro de Ciências da Saúde, Departamento de Enfermagem. Avenida Salgado Filho, S/N, Lagoa Nova, Natal/RN, Brasil. CEP: 59078970. Fax: [phone].
E-mail: [e-mail]