Global Burden and Attributable Risk Factors of Acute Lymphoblastic Leukemia in 204 Countries and Territories from 1990-2019: Estimation Based on Global Burden of Disease Study 2019

Purpose: To provide a foundational guideline for policy-makers to e�ciently allocate medical resources in the context of population aging and growth, a latest spatial distribution and temporal trend of acute lymphoblastic leukemia (ALL) along with attributable risk factors by sex and age were mapped. Methods: Based on the Global Burden of Disease Study 2019, we calculated the estimated annual percentage change (EAPC) values to quantify temporal trends in morbidity and mortality of ALL. We used applied Spearman rank correlation to estimate the relationship between the EAPC and potential in�uence factors. The population attributable fraction of potential risk factors for ALL-related disability-adjusted life years (DALYs) were estimated by the comparative risk assessment framework. Results: We found that new ALL cases increased signi�cantly by 129% worldwide, and the age-standardized incidence rate (ASIR) increased by 1.61 percent per year. The proportion of elder patients sharply increased, especially within the higher socio-demographic index (SDI) region. Smoking and high body mass index remained the predominant risk factors for ALL-related mortality. Notably, the contribution of high body mass index presented an increasing trend. Conclusion: The global burden of ALL has steadily increased, especially in middle SDI region. Health measures should be taken into consideration to improve the treatment of elders with ALL due to a great proportion in the higher SDI region. Attention should be paid to the environmental problems caused by industrial development in low SDI areas.


Introduction
Leukemias are a group of malignant clonal disorders that originate in hematopoietic stem cells and are characterized by an increased number of leucocytes in the blood and/or the bone marrow (Juliusson and Hough 2016).Acute lymphoblastic leukemia (ALL) is a common subtype of leukemia presented with chromosomal abnormalities and genetic alterations involved in differentiation and proliferation of lymphoid precursor cells (Florent Malard 2020).The reported incidence of ALL is 1.7 cases per 100 000 individuals per year within the USA, with approximately 6 150 new cases estimated in 2020, exceeding the 5 970 new cases in 2017.In the world, new cases had reached 153 320, with age-standardized morbidity reaching 1.96/100 000 by 2019.It is frequently diagnosed in children and young adults, with incidence peaks between 1 and 4 years of age.Notably, the incidence of ALL in the elderly is also increasing each year (Florent Malard 2020; Dong et al. 2020; 'National Cancer Institute.Cancer Stat Facts: Leukemia -Acute Lymphocytic Leukemia (ALL)').
Although the mechanisms of ALL are not completely understood, several factors are thought to be involved, such as ionizing radiation (a causal exposure was established in childhood ALL), infection (the rst indicated and the strongest candidate for the cause of ALL) and inherited susceptibility.At present, the rst-line treatment of ALL typically comprises 3 phases: remission-induction, intensi cation (or consolidation), and continuation (or maintenance) (Inaba, Greaves, and Mullighan 2013; Terwilliger and Abdul-Hay 2017; Network).More than 80% of children between 1 and 18 years of age are expected to relieve effectively (Vrooman and Silverman 2016;Pui et al. 2009;Veerman et al. 2009), but only 30% to 40% of rst salvage and 10% to 20% of second salvage regimens achieve complete remission (Gregory 2019;Ronson, Tvito, and Rowe 2016).Adult patients relapse rate was still high (Linker et al. 1987), and 20% of children experienced a relapse (Vrooman and Silverman 2016).Hence, the heterogeneity of the ALL-related burden internationally is profound.Analysis of the global burden of ALL by region, sex and age will provide important guidance for its biology, prevention and treatment.
The Global Burden of Diseases (GBD) Study 2019 comprehensively collected an extensive set of data sources and applied novel statistical methods to estimate the incidence, mortality and disability-adjusted life years (DALYs) caused by various diseases along with corresponding risk factors in 204 countries and territories from 1990 to 2019 (Pourshams et al. 2019).Given the disease burden of ALL is unclear across geographies, we conducted this study to investigate the number of incidence cases, deaths, DALYs, and corresponding age-standardized rates of ALL.Moreover, we presented the changes in ALL-related DALYs attributed to potential risk factors.Our research can inform policy-makers on how to allocate limited public health resources reasonably and effectively.

Study data
The GBD 2019 study estimates 369 diseases burden along with 87 risk factors in 204 countries and territories by gender, age group, and location.The detailed methods for the statistical estimation could be found on the supporting website, http://ghdx.healthdata.org/gbd-2019/code(Collaborators 2020a; Collaborators 2020b).In brief, the cancer burden estimation in the GBD study was originated from various national cancer registries and aggregate cancer database registries, such as Cancer Incidence in Five Continents (CI5), Nordic Cancer Registries database (NORDCAN), Surveillance, Epidemiology, and End Results (SEER).All ICD-9 and ICD-10 codes pertaining to ALL (204.0-204.02and C91.0-C91.02,C91.2-C91.32,C91.6-C91.62,respectively) were included in these estimates.The 95% uncertainty intervals (UIs) for all estimates in the GBD Study were calculated based on the 25th and 975th ordered values of 1,000 randomly selected posterior distributions.All geographical regions around the world were categorized into 21 GBD regions (e.g.High income North America) and seven super GBD regions (e.g.High income).Based on socio-demographic index (SDI) distribution, countries and territories were further divided into ve SDI regions, including high, high-middle, middle, low-middle, and low SDI regions.The SDI is a comprehensive indicator re ecting the level of health development, which integrates per capita income, education level, and fertility rate.We retrieved annual numbers and rates of incidence cases, deaths, and disability-adjusted life years (DALYs) of ALL by sex, location, and age group (5-year groups within the ages of 0 to 94 years, and ≥95 years) from the Global Health Data Exchange (GHDx) website, http://ghdx.healthdata.org/gbd-results-tool.Age-standardized rates (ASRs) were estimated according to the WHO 2001 world population distribution.We further downloaded the annual SDI information of each region for correlation analysis.According to the GBD database, four well-judged risk factors contributed to ALL burden, including smoking, high body mass index, occupational exposure to benzene, and occupational exposure to formaldehyde.The attributable burden of potential risk factors in the GBD Study was calculated based on the comparative risk assessment framework with six steps: identifying cogent risk-outcome pairs, estimating relative risk using systematic review, collecting the spatial exposure levels, determining the theoretical minimum level of exposure, calculating the population attributable fractions, and assessing combined attributable proportion by considering the mediating effect (Collaborators 2020b).

Statistical analysis
To avoid interference from changes in age distribution and population sample size, we used the ASR to estimate the difference in the burden of ALL by year, sex, and region.The annual change trend of the burden of ALL was quanti ed using the estimated annual percentage change (EAPC), which was calculated with a regression line, y = α + β×x + , where y was de ned as ln(rate) and x was de ned as the calendar year (

Incidence tendency and variation in ALL
Globally, new cases of ALL increased from 66 810 in 1990 to 153 320 in 2019, and the ASIR increased by 1.61 per year (95% CI 1.52~1.71)during this period (Table 1).Males had more opportunities to suffer from ALL than females.And the male-to-female ratio was 1.24 in 1990, then 1.22 in 2019 (Additional le 1: Fig. S1A).Although the ASIR of both sexes continued to climb, males' ASIR increased more quickly than females' in most age groups (Table 1, Additional le 1: Fig. S2A).
When we compared SDI regions, the middle SDI region had the highest incidence in 1990 (17 450 cases), while the high-middle SDI region had the highest in 2019 (52 070 cases), with the most rapid growth of ASIR (ASIR: 1.51 in 1990 and 3.39 in 2019, EAPC = 3.08, 95% CI 2.79~3.37;Table 1, Additional le 1: Fig. S3A).High SDI region always had the highest ASIR, and had a signi cant upward trend from 1990 to 2019 (ASIR: 1.02 in 1990 and 3.52 in 2019, EAPC = 1.72, 95% CI 1.44~2).To our delight, the ASIR of ALL decreased in low-middle and low SDI regions, the latter had the lowest incidence burden (Additional le 1: Fig. S1A, Table 1).For GBD regions, East Asia had the highest incidence in 2019, followed by Western Europe, with 58 110 and 29 590 cases, respectively.At the same time, East Asia had the greatest increase in ASIR (EAPC: 5.86, 95% CI: 4.87~6.86),followed by High-income Asia Paci c and Central Europe (Table 1).Notably, South Asia and Central Asia had the most rapid decrease in ASIR of ALL.
At the country or territory level, San Marino had the highest ASIR in 2019 (23.28), 122 times greater than the lowest ASIR (0.19 in Namibia).The ASIR of ALL in four other countries, Italy, Andorra, Monaco, and Spain, was more than 7.0 (Fig. 1A, Additional le 2: Table S2).Further, Taiwan (Province of China) had the fastest growth in ASIR (EAPC = 8.19, 95% CI 7.52~8.88),and Guatemala, South Korea, and Cyprus also presented an obvious increase in ASIR, with all EAPCs above 7.0 (Fig. 1C, Additional le 2: Table S3).

Death tendency and variation in ALL
In general, ALL-related deaths increased slightly from 41 240 in 1990 to 47 650 in 2019, while the ASDR of ALL decreased slightly by 0.57 per year from 0.76 in 1990 to 0.63 in 2019 (Table 2).The number of males died from ALL was 23 950 in 1990 and 28 170 in 2019, higher than females (17 300 in 1990 and 19 480 in 2019).We found the ASDR in both sexes has been decreased, at an annual trend of 0.78/year in females and 0.43/year in males (Table 2, Additional le 1: Fig. S1B).When comparing regions, the most deaths occurred in the middle SDI region (17 080 deaths in 2019), with the highest ASDR (ASDR: 0.74, 95% CI 0.57~0.83)and fastest-growing ASDR (EACP: 0.14, 95% CI 0~0.28).The other four regions showed a decreased tendency.Subgroup analysis of geographical zone indicated that East Asia (8 620 cases) and South Asia (6 910 cases) had the most deaths, with a positive ASDR of 0.94 and a negative ASDR of 1.45, respectively.Also, East Asia had the fastest rise in ASDR countries and territories with SDI more than 0.7 in 2019, the corresponding ASDR dropped obviously, which indicated the treatment protocol in high SDI region would be worth learning and promoting in other areas.For EAPC of DALYs, a similar characteristic to ASDR is shown in Additional le (Figure S3).
We then investigated the correlation between SDI and ASIR, ASDR, and age-standardized DALYs rate in 21 GBD regions.Results showed that annual ASIR had remained relatively stable with SDI progressing in most low-burden GBD regions; however, the ASIR presented a steep increase in most high-burden GBD regions, especially East Asia, Western Europe, and High-income Asia Paci c (Fig. 3A).Inversely, the ASDR and age-standardized DALYs rate markedly dropped with SDI development in most GBD regions, especially in high SDI region.Notably, the ASDR and age-standardized DALYs rate rose beforehand and decreased afterward in Central Latin America and Andean Latin America (Fig. 3B, Additional le 1: Fig. S6).

Age characters of ALL
We divided the population into 20 groups according to ages in the global and SDI regional areas: patients aged 0~90 years old were divided into 19 groups, with a component gap of 5-years, and the nal group was above 95 years old.Globally, children aged 0~9 years old and the elderly were the most vulnerable populations according to incidence and death rates (Additional le 1: Fig. S7A-S7C), but which presented an obvious disparity referring to SDI regions (Fig. 4A-4B, Additional le 1: Fig. S8).In low-middle and low SDI regions, the ALL burden focused on the population under 25 years old.Conversely, the proportion of patients aged 25 years and older increased gradually from 1990 to 2019 among both sexes in the remained three SDI regions (Fig. 4A, Additional le 1: Fig. S8).In addition, the incidence rate of ALL in young people usually decreased, but increased among the elderly, whose ASIR had almost twice as many as children in 2019 (Fig. 5A, Additional le 1: Fig. S9A).Death rate and DALYs rate in children remained high, but the older patients' death rate became much higher, even exceeding children, showing a positive correlation with age (Fig. 5B, Additional le 1: Fig. S9B-S9C, S10).The rate of increase in adults was also the fastest; EAPCs of 25-69 years old patients were around 2.5 from Additional le (Figure S2A).
Particularly, middle SDI region patients (both sexes) over 60 years old had a higher EAPC in agestandardized death/DALYs rate, while EAPC in children was under 0, presenting hopeful treatment strategies (Additional le 1: Fig. S3B-S3C, S2).

Risk factors contributing to ALL-related deaths or DALYs
Smoking was the predominant contributor to ALL-related DALYs for males across the world, while high body mass index was the main cause of ALL-related DALYs for females in 2019 (Fig. 6A-6C).In high SDI region, the role of smoking in females ALL-related DALYs was greater than the role of high body mass index (Fig. 6B-6C).Occupational exposure to formaldehyde gradually became an important factor from 1990 to 2019, especially in middle, low-middle, and low SDI regions (Fig. 6).Subgroup analysis of the GBD geographic zone suggested that the ratio of high body mass index accounted for an increasing proportion of all risk factors from 1990 to 2019 (Additional le 1: Fig. S11).

Discussion
In our study, we comprehensively analyzed the global, regional, and national burden in incidence, deaths, and DALYs of ALL along with the temporal trend over the past 30 years in 204 countries and territories.
Globally, ALL incidence and deaths have increased, with an increased ASIR and a decreased ASDR, respectively.But both DALYs and ASR of DALYs were declined.Before our study, two articles have analyzed the global burden of ALL based on the database of GBD 2017 (Ou et al. 2020; Ming Yi 2020).
whose results differed from our study in some aspects due to different methods or differential data sources of GBD 2017.The latest methods and data sources based on GBD 2019 made some optimizations and updates compared to GBD 2017.First, GBD 2019 added the updated cancer mortality, which made the estimation on ALL reconstructed by mathematical models more robust.Second, to acquire more training data and less smoothing across time and geography, the mortality-to-incidence ratio estimation was updated with lower case inclusion criteria and different model hyperparameters.And third, the covariates used in CODEm models were adjusted for GBD 2019.These modulations make our study more comprehensive and precise.For example, the GBD 2017 illustrated almost no change for ASIR of around 0.87/100 000, but the ASIR was increased by 1.61 per year from 1.23/100 000 in 1990 to 1.96/100 000 in 2019 in our results.
Our ndings demonstrated the incidence cases of ALL increased by 1.29% in the past 30 years.That might be due to the change in its diagnostic criteria (The diagnostic criteria for bone marrow blasts decreased from ≥30% to ≥20%), or because more and more doctors started to recognize and diagnose ALL at the early stage.Our data also suggested that we have made great progress in treatment and management, but much remains to be done in prevention.However, the current burden and change trend of ALL varies greatly with more than 100 times across the countries and territories, which makes the ALL's burden control more complex.Notably, in most high burden areas of ALL, the growth trend was more obvious, especially in East Asia and Western Europe.Therefore, understanding the exact pattern of the causes of ALL is key to prevention and treatment.
According to our studies, male patients were more likely to be suffering from ALL than females, and the difference between sexes further widened from 1990 to 2019.Geographically, middle SDI region had the highest incidence and the most rapid ASIR.We found that Western Europe and high-income Asia Paci c regions had the highest ASIR, while Latin America had the highest ASDR and age-standardized DALYs rate, for reasons that have not yet been studied previously.Nationally, when studying the correlation between SDI and ASIR, ASDR and age-standardized DALYs rate, we found a signi cant positive correlation between the EAPC of ASIR and baseline ASIR in 1990 and SDI in 2019.However, the converse relationship between EAPC of ASDR and baseline ASDR in 1990 and SDI in 2019 were observed.This re ects the disparate problem as trends in morbidity and mortality.It may be that in these middle or lowmiddle areas that industrialization has led to a rise in environmental carcinogens, like benzene.But the prognosis of ALL has been improved greatly in developed countries because of improved medical care and affordable treatment.
In most regions, patients aged 0~9 years still have a higher incidence.Based on previous work, inherited genetic variants probably contributed directly to a genetic vulnerability of hemopoietic cells (Florent Malard 2020; Trevino et al. 2009).IKZF1, ARID5B, CEBPE, CDKN2A, ETV6, and PAX5 were believed to signi cantly and consistently be associated with childhood ALL ( However, with the global aging population, in the 25-69 years old patients, a gradual increase was seen in incidence cases and ASIR from 1990 to 2019.Aging has previously been associated with a functional decline of hematopoietic stem cells (HSC) as well as an increased risk of myeloid malignancies (Liu et al. 2019).In 2019, patients over 50 years of age accounted for almost half of all patients in the high SDI region, which may due to a long lifespan.A long lifespan could increase the incidence of many diseases, not only ALL.And this proportion represented a small percentage of patients in low-middle and low SDI regions.This may be due to the reduced economy and fewer medical options and an incomplete registration system in low SDI region.However, based on the data we have, health management of older adults should be a priority in high, high-middle, and middle SDI areas.In this situation, older patients' worse prognosis is also an obstacle of ALL's treatment.In recent years, the development of novel drugs, such as blinatumomab, rituximab, tyrosine kinase inhibitors, CAR-T cells, and others, have improved the ).We believe these novel therapies will provide a bright landscape for ALL treatment.
Based on the GBD database, we analyzed four possible factors attribute to ALL-related deaths and DALYs.Smoking was the rst and second reason in males and females in 2019, respectively.According to the World Health Organization (WHO), there were 1.3 billion smokers in the world, and men were ve times more likely than women to smoke.A meta-analysis in 2019 reported that paternal smoking was signi cantly associated with the elevated risk of childhood ALL during pregnancy, but maternal smoking was not (Goldstein 2010).No studies have linked smoking with morbidity and mortality in older patients.
Tobacco smoke contains more than 4000 chemicals including a myriad of known carcinogens.It has been reported that smoking is associated with an accumulation of cadmium and lead in seminal plasma, reduced sperm count and motility, and fewer morphologically normal sperm (Heck et al. 2019; Jiang, Wu Sy Fau -Ke, and Ke 2016).
For females, high body mass index was the rst contributor to ALL-related deaths and DALYs.A large cohort study in Mexican children suggested that overweight and obese patients embody a subgroup with a high risk of dying during leukemia treatment (Jabo et al. 2017).The mechanisms of obesity leading to ALL may include (1) hyperinsulinemia associated with obesity-induced insulin resistance, (2) interstitial levels of adipocyte-released fuels that are likely extremely high in the adipose tissue microenvironment, and/or (3) obesity associated with chronic in ammation, a well-known contributor to solid tumor oncogenesis (Orgel, Sea, and Mittelman 2019).Notably, with the improvement of life quality, high body mass index gradually accounted for a bigger proportion of all factors.Therefore, we should focus more on the dietary structure of ALL patients, especially in high SDI region.
Benzene, a chemical reagent, has been documented to lead to a broad range of genotoxic effects in lymphocytes of benzene-exposed workers, and has chromosomal effects in carcinogenesis (Goldstein 2010).A population-based study identi ed that maternal occupational exposure to benzene during pregnancy was related to increased risk of ALL in offspring (adjusted OR = 2.28, 95% CI 1.17 to 4.41) (Heck et al. 2019).As similar to benzene, it has been reported that the median formaldehyde and benzene concentrations in ALL (32.120 pg/ml) were signi cantly higher than those in controls (18.705pg/ml) (Jiang, Wu Sy Fau -Ke, and Ke 2016).Notably, occupational exposure to formaldehyde gradually became an important factor from 1990 to 2019, especially in the low-middle and low SDI regions, where industrialization is developing rapidly.This nding may remind policy-makers to prioritize environmental protection as well as development.
Besides the above-mentioned risk factors, neighborhood socioeconomic status (nSES), marital status and race would in uence ALL treatment.It has been reported that lower nSES quintiles predicted lower chemotherapy and hematopoietic cell transplantation utilization for ALL.Compared to married patients, never married patients had a lower RR of receiving chemotherapy or hematopoietic cell transplantation.
Lower HCT utilization occurred in Hispanic and non-Hispanic black patients when compared to non-Hispanic whites, which explained racial differences (Jabo et al. 2017).
To our knowledge, we reported the latest burden of ALL across the world, which provides an evidencebased assessment for the formulation of ALL management strategies at the global, regional, and even national levels.However, some limitations need to be mentioned in our study.Firstly, the reconstructed data may be not accurate in some countries with sparse prior information, but the robust estimation performed by the GBD study has somewhat alleviated this concern.Moreover, the speci c pathogenesis and treatment for ALL need further basic research and clinical doctor's efforts.Finally, many attributions of risk factors are associated with ALL-related mortality, here we only analyzed the available four risk factors due to the restriction of the GBD study, and other risk factors require further analysis in the future study.In any case, the global burden of ALL is still increasing, and we should take active measures to minimize the harm of ALL to human beings.

Conclusions
Globally, the incidence burden was heavier than mortality.Although people aged 0~9 years were more likely to suffer from ALL, the increasing number of middle-aged and older patients cannot be ignored.Older adults accounted for a bigger proportion of all patients and had the worse prognosis; and given the Gocho and Yang 2019; Sherborne et al. 2010; Xie et al. 2014; Carl H. June 2018; June and Sadelain 2018; Michel Sadelain 2015; Kantarjian et al. 2017).Environmental factors like pesticide exposure, ionizing radiation and childhood infections are also important contributors to ALL's occurrence.Therefore, attention should be paid to the environmental problems caused by industrial development especially in low-middle and low SDI areas.

Figures Figure 1
Figures

Table 1
Incidence and age-standardized incidence rate per 100 000 people for ALL in 1990 and 2019.

Table 2
Deaths and age-standardized death rate per 100 000 people for ALL in 1990 and 2019.