Trend Analysis of Leukemia Mortality and Years of Life Lost (YLL) from 2004 to 2019 in the Fars Province, Iran

Background: Although the incidence of leukemia’s is not high, many of these cancers lead to death over a short period. This is a cross-sectional study on leukemia deaths in southern Iran. Methods: All deaths due to leukemia in the Fars province were obtained from the population-based electronic death registration system (EDRS). Crude and age-standardized mortality rate (ASMR), YLL, and YLL rate data were calculated, and joinpoint regression was used to examine the trend. Results: Totally, 3141 deaths from leukemia occurred in the Fars province during the study period (2004-2019). Of these, 61.5% (1933 cases) pertained to men. The crude mortality rate was 6.1 (95% CI: 5.8 to 6.4) in men and 3.9 (95% CI: 3.7 to 4.2) in women. Also, ASMR was 6.6 (95% CI: 6.3 to 6.9) and 4.2 (95% CI: 4.0 to 4.4) in men and women, respectively. The total YLLs due to leukemia were 32804 in men and 23064 in women. The joinpoint regression analysis demonstrated that the trend of YLL rate due to premature mortality was stable: the annual percent change (APC) was -1.2% (95% CI: -2.5 to 0.2, P=0.090) for males, and -1.0% (95% CI: -2.9 to 0.9, P=0.274) for females. Conclusion: The mortality and YLL due to leukemia had a stable trend. However, this trend has been decreasing or increasing in some age groups. Determining and controlling essential risk factors, especially the environmental factors of leukemia, may reduce its burden in the Fars province.


Introduction
Leukemia is a heterogeneous group of hematopoietic malignancies that include four main subtypes described by most cancer registries: acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphoblastic leukemia (CLL) and chronic myeloid leukemia (CML). 1 According to GLOBOCAN, in 2018, leukemia accounted for 437 033 cancer cases and 309 006 cancer deaths, thus becoming the 15 th most commonly diagnosed cancer and the 11 th leading cause of cancer-related death worldwide.Globally, men have a higher burden of leukemia than women.In 2018, the age-standardized incidence rate was 6.1 per 100 000 for men compared to 4.3 per 100 000 for women, and the mortality rate was 4.3 per 100 000 in men compared to 2.8 per 100 000 for women. 2 According to the GLOBOCAN Cancer 2020, leukemia accounts for 2.5% of all new cancer cases and 3.1% of all cancer deaths. 3The lowest incidence of leukemia pertains to Central and West Africa (less than 3 per 100 000 in men and less than 2 per 100 000 in women), and the highest to North America and Australia/ New Zealand (more than 10 per 100 000 men and 7 in 100 000 women).The estimated low incidence in sub-Saharan Africa may be due to the under-diagnosis of the disease in the elderly or very young patients. 4Leukemia is the cause of 8% of all cancer cases.It affects all age groups with different prevalence and incidence rates in Iran and the whole world and causes significant mortality and high costs for the diagnosis and treatment process. 5lthough the overall incidence is low, leukemia is the most common type of childhood cancer, accounting for 30% of all cancers diagnosed in children under 15 years of age. 6lthough the incidence of leukemia's is not high, many of these cancers lead to death over a short period. 7Cancer in Iran is the third cause of death after cardiovascular diseases and traffic accidents, accounting for 20% of deaths.Investigating leukemia in further research in Iran indicates the geographical diversity of risk factors in different provinces. 8In Iran, registration of incidence rates has shown that leukemia is the seventh most common cancer after skin, breast, stomach, colon, bladder, and prostate cancer. 9he years of life lost (YLL) are an essential criterion for ranking the health status of a society and observing its challenges.According to the World Health Organization report, the value of one year of life is three times more than the gross domestic product (GDP) per capita of any country. 10The latest Global Burden of Diseases study showed that the trend of YLL due to leukemia was decreasing worldwide. 11In Brazil, between 2001 and 2019, more than 2.2 million YLLs due to leukemia were reported. 12In a study conducted in Iran in 2016, leukemia was the third cause of YLL after stomach and lung cancers. 13Without understanding the burden of cancer and prioritizing based on it, it will not be possible to implement, monitor, and adequately plan interventions for cancer prevention and control.As a result, this study analyzed the mortality rate and YLL due to leukemia in the Fars province.

Materials and Methods
This cross-sectional study was conducted in the Fars province from 2004 to 2019.We extracted all leukemia deaths from the population-based electronic death registration system (EDRS) by age, sex, and year of death and according to ICD-10.The code used in this study was C91-C96.In the population-based EDRS, we used all available sources to detect, record, and collect deathrelated information. 14Repeated deaths, identified based on the father's name and national identification number, were excluded from the study.
The total estimated population'of the Fars province was calculated using the primary data of health centers and the population and housing census from 1996 to 2016, taking into account the annual population growth.For standardization, the standard population of 2013 for countries with low and middle income was used. 15

Statistical Analysis
First, crude and age-standardized mortality rates (ASMR) of leukemia were calculated during the study years according to age and sex groups.
Then, to calculate YLL, using the standard life table and determining the life expectancy for different age and sex groups, as well as the number of deaths due to leukemia, in each age and sex group, and based on the following relationship, the calculation was made. 16,17L = N Ce (ra) Where N = number of deaths in an age and gender-specified group; L = life expectancy of death cases in the same age and gender group; r = Discounting Rate, that is 0.03; β = a conventional rate in calculating age value which equals 0.04; C = 0.1658, which is an adjusted, constant value; a = the age when death occurred; and e = a constant value considered as 2.71.
The number of YLLs due to premature death caused by leukemia was analyzed using the YLL template of 2015, World Health Organization (WHO), in Excel version 2016.
Joinpoint regression based on the log-linear transformation was used to evaluate the trend of crude and age-standardized mortality and YLL rates for different years.Joinpoint regression analysis demonstrates changing trends over successive segments of time and the increase or decrease of each part.The resulting line segment between joinpoints is described by the annual percent change (APC) based on the line segment's slope and the average annual percent change (AAPC).Unlike pitch-based linear regression, log-linear regression is based on the APC.(i.e. the rates change at a constant percent per year), and can also be used to study trends across scales. 18The joinpoint regression model can be written as follows: Where ti indicates the time points (2004, 2005… 2019), yi represents the YLL rates, K shows the number of change points, β0, β1 and γ1… γk indicate the regression coefficients, and εi is the model error term.By fitting the joinpoint regression, we can calculate the APC in rates between the estimated change points.To do this, the log transform of the model is utilized.APC = 100 × (exp (β1 + 1* I ( -) + … + *I ( -)) -1). 19n our analysis, X i represented the years between 2004 and 2019, and y i is the annual burn YLL rate.
We used constant variance (homoscedasticity) and uncorrelated in our analysis.The Joinpoint Regression Program 4.9.1.0was used to perform the analysis for the trend. 20

Discussion
This study investigated the mortality rate trend and YLL due to leukemia in 16 years from 2004 to 2019 in southern Iran.In this period, the total number of YLLs due to leukemia in the entire study population was 0.89 per 1000, which was higher in men than in women (1.04 per 1000 vs. 0.74 per 1000).However, the average number of YLL due to leukemia was higher in women than men (19.09 vs. 16.97 years).In 2004, the YLL rate was 1.18 per 1000 in men, and 0.74 per 1000 in women.In 2019, the rate of YLL decreased to 0.84 per 1000 in men and 0.62 per 1000 in women.
Although this decreasing trend was insignificant in men and women, it was significant in general (APC = -1.2,P value = 0.090) for men; APC = -1.0,P value = 0.274 for women; and APC = -1.1,P value = 0.048 overall).In age groups, different changes were observed in the trend of mortality in men and women, such that in the age group of 0-44 years, this trend was constant in men, but decreased in women.In the age group of 45-59 years, this trend decreased in men but was stable in women.In the age group over 75 years, the mortality trend due to leukemia was increasing in men, but decreasing in women.In the age group of 60-74, this trend was constant in both sexes.
One study showed that on the global scale, the trend of ASMR was decreasing from 1990 to 2017.In recent decades, there have been significant changes in leukemia mortality worldwide, such that mortality has decreased in all age groups.According to the WHO statistics, the death rate from this cancer among all age and sex groups is decreasing in countries such as France, Italy, Great Britain, and Japan. 21Also, the death and morbidity of leukemia have decreased in most regions and countries with a high socio-demographic index (SDI), such as Bahrain, Finland, and Austria. 11lthough leukemia is diagnosed at a younger age in low-and middle-income countries, the survival interval of leukemia has gradually decreased in most countries. 22,23he 2019 GBD study reported that the age-standardized rate (ASR) of death and disability-adjusted life years (DALYs) attributable to four major leukemia subtypes decreased from 1990 to 2017. 24In the present study, a decreasing trend of age-standardized mortality was observed from 2004 to 2019, and the ASR of death in 2004 was equal to 7.7 in men and 5.2 in women, which in 2019 was reduced to 6.3 in men and 3.7 in women.The decrease in the death rate and YLL of leukemia is most likely due to the new methods and strategies for diagnosing and treating leukemia.In our study, similar to other studies, the burden of leukemia was greater in men than women. 11,24,25In other studies, a relationship between leukemia and smoking has been established. 26,27t has been shown that the higher burden of leukemia in male patients compared to female patients may be due to exposure to smoking and other high-risk occupational and environmental factors. 28In addition, a national study in the United States found that leukemia deaths decreased in states where smoking rates decreased but remained unchanged in states where smoking prevalence remained relatively constant. 29n a study in Europe, it was shown that the trend of mortality due to leukemia from the years 1970 to 2009 decreased in most European countries, and the age group of 0-14 witnessed the most significant decrease (AAPC = -3.7%)for men and (-3.8%) women.Also, in the age group of 15-44 years, AAPC was -2% for both sexes.In the rest of the age groups, the mortality trend caused by leukemia was decreasing. 30The findings of this study in some age groups align with ours and contradict the results of our research in some other age groups.
Different trends in leukemia mortality in later age groups are also attributed to the different histotype compositions of leukemia at different ages: ALL is the most common type in children and young adults, while CLL prevails in adulthood. 30n the past decades, significant advances have been made in the treatment of leukemia and the prognosis related to  its treatment, which has led to a significant change in the survival pattern of leukemia patients.In recent decades, very good treatments for leukemia have been developed and improved, such that the 5-year survival rate for children and adolescents is reported to be 84%. 31It should be noted that the disease burden is different across regions and countries.Demographic factors and socioeconomic status affect the disease burden. 32It has been shown that the apparent downward trend in leukemia death in areas with high SDI and regions with high income can be due to adequate medical resources and the health care system. 11,33he decreasing trend in age-standardized mortality and YLL observed in this study largely depends on the development of health care in Iran.The comprehensive coverage of primary health care in the villages of Iran created a revolution in population health indicators and reduced inequalities. 34Thus, in Iran, primary health care covers a large population in rural areas, and health facilities available to villagers are inexpensive.In this regard, insurance services have been provided to villagers as well  as city residents without health insurance.According to the family physician program and rural insurance in Iran, the existing primary health care network is an essential asset in facilitating the implementation of the family physician program in rural areas, 35 which can significantly improve people's health.
A limitation of the present study was that YLL was not evaluated throughout Iran due to the unavailability of the necessary data.This study was of high quality and with a strong study design, large sample size, and extensive time period of data analysis.

Conclusion
The trend of mortality and YLL due to leukemia in the study period had a relative decrease, which was not statistically significant and was almost constant.However, this trend was decreasing or increasing in some age groups.Determining and controlling important risk factors, especially the environmental factors of leukemia may reduce its burden in the Fars province.In addition, the use of modern and efficient leukemia treatment methods can prevent a significant number of deaths.Analytical studies are recommended to obtain the causal relationship and solve the problems related to the disease.

Figure
Figure 1.Mortality Rate Due to Leukemia by Gender and Age Groups Figure 2. Years of Life Lost Rate Due to Leukemia by Gender and Age Groups

Figure 3 .
Figure 3. Trend of Years of Life Lost Due to Leukemia in Women During the Years 2004-2019

Figure 4 .
Figure 4. Trend of Years of Life Lost Due to Leukemia in Women During the Years 2004-2019

Table 1 .
Crude and Age-Standardized Mortality Rate (Per 100 000 Population) and Years of Life Lost due to Leukemia by Gender and Year in the Fars Province During 2004-2019 1. Mortality Rate Due to Leukemia by Gender and Age Groups Figure 2. Years of Life Lost Rate Due to Leukemia by Gender and Age Groups