Global, regional, and national burdens of leukemia from 1990 to 2017: a systematic analysis of the global burden of disease 2017 study

Global level

There were approximately 2.43 million (95% UI 2.19 million to 2.59 million) prevalent cases of leukemia, with an age-standardized prevalence rate (ASPR) of 32.26 (95% UI 29.02 to 34.61) per 100,000 population in 2017. The estimated annual percentage change (EAPC) in the ASPR was 0.22% (95% CI 0.13 to 0.31, P<0.01) at the global level from 1990 to 2017. The DALYs attributable to leukemia were stable over the past 28 years, while the age-standardized DALY rate decreased significantly, with an EAPC of -1.52% (95% CI -1.60% to -1.44%, P<0.01), decreasing from 225.37 (95% UI 259.26 to 190.20) to 156.83 (95% UI 168.08 to 140.81) per 100,000 population. In addition, there were approximately 0.52 million (95% UI 0.47 million to 0.55 million) incident cases of leukemia in 2017, with an age-standardized incidence rate (ASIR) of 6.76/100,000 (95% UI 6.15 to 7.16) population and an EAPC of -0.42% (95% CI -0.48% to -0.38%, P<0.01) from 1990 and 2017. Globally, approximately 0.35 million (95% UI 0.32 million to 0.36 million) deaths were attributable to leukemia, with an age-standardized death rate (ASDR) of 4.50 (95% UI 4.12 to 4.73). The ASDR decreased by -1.04% (95%CI -1.10% to -0.99%, P<0.01) (Table 1 and Figure 1A–1D). The cases and ASRs in other regions, including low-, low-middle-, middle-, and high-SDIs regions, are showed in Supplementary Figure 1.

Regional level

Regionally, the highest ASIRs of leukemia per 100,000 population in 2017 were in East Asia (10.54 (95% UI 8.81 to 11.71)), Australasia (9.62 (95% UI 8.33 to 11.02)), and Western Europe (8.86 (95% UI 8.36 to 9.35)). The lowest values were in west sub-Saharan Africa (3.40 (95% UI 2.76 to 4.01)), central sub-Saharan Africa (3.87 (95% UI 2.90 to 4.60), and south Asia (3.99 (95% UI 3.46 to 4.48)). East Asia (81.97 (95% UI 66.17 to 93.10)), Australasia (60.56 (95% UI 51.70 to 70.58)), and Western Europe (49.93 (95% UI 51.70 to 70.58)) had the highest ASPRs per 100,000 population in 2017, whereas western sub-Saharan Africa (10.78 (95% UI 8.75 to 12.92)), south Asia (11.71 (95% UI 10.02 to 12.92)), and central sub-Saharan Africa (11.76 (95% UI 8,41 to 14.41)) had the lowest ASPRs. East Asia had the highest ASIR EAPC at 0.83% (95% CI 0.63% to 1.02%, P<0.01) and the highest ASPR EAPC at 2.95% (95% CI 2.64% to 3.26%, P<0.01), while Australasia had the lowest ASIR EAPC, at -1.65% (95% CI -1.92% to -1.38%, P<0.01) and the lowest ASPR EAPC, at -0.96% (95% CI -1.36% to -0.66%, P<0.01). The EAPCs in the ASIR and ASPR for most of the regions during 1990-2017 showed decreasing trends (Table 1).

Generally, the ASDRs and age-standardized DALY rates per 100,000 population in all regions decreased over the past three decades, with the largest of ASDR EAPC in East Asia (-2.20% (95% CI -2.42% to -1.97%, P<0.01)) and age-standardized DALY EAPC in East Asia (-2.85% (95% CI -3.12% to -2.56%, P<0.01)). Oceania (212.31 (95% UI 165.99 to 268.26)), Andean Latin America (202.22 (95% UI 162.76 to 228.16)), and Southeast Asia (198.24 (95% UI 168.14 to 215.67)) had the highest age-standardized DALY rates in 2017. Conversely, the age-standardized DALY rates were lowest in high-income Asia Pacific (96.33 (95% UI 90.10 to 103.09)), Western Sub-Saharan Africa (109.20 (95% UI 88.75 to 129.33)), and Southern Sub-Saharan Africa (118.02 (95% UI 88.75 to 129.33)) (Table 2).

National and territorial level

The ASIRs of leukemia during 1990-2017 varied across 195 countries and territories. These rates ranged from 2.56 to 14.83 per 100,000 population in 2017. Syria (14.83 (95% UI 12.15 to 17.71)), the United Kingdom (12.13 (95% UI 11.68 to 12.58)), and Denmark (11.98 (95% UI 10.41 to 13.82)) were the countries with the highest ASIRs in 2017. Malawi (2.56 (95% UI 1.94 to 3.06)), Morocco (2.74 (95% UI 2.20 to 3.29)), and Uganda (2.82 (95% UI 2.23 to 3.29)) had the lowest ASIRs of leukemia. The ASIR EAPCs from 1990 to 2017 differed substantially among countries and territories. Slovakia (1.80% (95% CI 1.59% to 2.00%, P<0.01)), Jamaica (1.52% (95% CI 1.02% to 2.02%)), and Taiwan (Province of China) (1.39% (95% CI 1.24% to 1.52%, P<0.01)) showed the largest significant increases. Bahrain (-2.60% (95% CI -3.04% to -2.16%, P<0.01)), Iraq (-1.92% (95% UI -2.23% to -1.62%, P<0.01)), and Moldova (-1.81% (95% UI -2.06% to -1.56%, P<0.01)) showed the steepest decreasing trends.

The ASPR of leukemia in 2017 varied from 7.98 to 83.51 cases per 100,000 population. China (83.51 (95% UI 67.27 to 95.01)), Denmark (74.53 (95% UI 63.06 to 86.57)), and Slovakia (66.52 (95% UI 50.70 to 81.89)) had the highest ASPRs in 2017. Mongolia (7.98 (95%UI 6.22 to 10.30)), Malawi (8.08 (95%UI 5.79 to 10.08)), and Cote d’Ivoire (8.41 (95%UI 6.48 to 10.30)) had the lowest rates. Slovakia (3.60% (95% CI 3.39% to 3.81%, P<0.01)), Taiwan (Province of China) (3.00% (95% CI 2.75% to 3.25%, P<0.01)), and China (2.97% (95% CI 2.66% to 3.28%, P<0.01)) had the greatest increase from 1990 to 2017. Ghana (-2.14% (95% CI -1.69% to -2.59%, P<0.01)), Equatorial Guinea (-2.09% (95% CI -1.80% to -2.38%, P<0.01)), and Kyrgyzstan (-1.99% (95% CI -1.83% to -2.15%, P<0.01)) had the greatest decreases. The ASPRs in 2017 and the related EAPCs among 195 countries and territories are presented in Figure 2.

The countries with the highest ASDRs of leukemia in 2017 also had the highest age-standardized DALY rates, as did the countries with the lowest ASDRs. Syria, Honduras, and Afghanistan had the highest ASDRs per 100,000 population at 13.72 (95% UI 10.56 to 16.52), 9.82 (95% UI 7.96 to 12.06), and 9.74 (95% UI 7.29 to 13.16), respectively. The largest decreases in ASDRs during the 1990-2017 period were observed in Bahrain (-3.00% (95% CI -3.49% to -2.53%, P<0.01)), Finland (-2.73% (95% CI -2.98% to -2.48%, P<0.01)), Australia (-2.35% (95% CI -2.61% to -2.08%, P<0.01)), while Bahrain (-2.99% (95% CI -3.42% to -2.55%, P<0.01)), China (-2.93% (95% CI -3.23% to -2.63%, P<0.01)), and South Korea (-2.78% (95% CI -2.90% to -2.67%, P<0.01)) also showed the largest decreases in age-standardized DALY rates over the past 28 years. The details of the EAPCs for the other 195 countries are listed in Supplementary Table 4 and Supplementary Figures 2, 3.

Similar to the trends of prevalent cases and ASPRs worldwide, high-middle-SDI countries and territories had consistently increasing numbers of prevalent cases and ASPRs, and the values in 2017 were almost double those in 1990. The EAPC in the ASPR in high-middle-SDI countries and territories was 2.52% (95% CI 2.37% to 2.66%, P<0.01). The number of incident cases and the ASIR in high-middle-SDI countries and territories increased from 80,397 (95% UI 67,571 to 87,985) and 7.59 (95% UI 6.44 to 8.27) to 123,669 (95% UI 106,234 to 132,373) and 8.68 (95% UI 7.43 to 9.46), respectively. The number of deaths in high-middle-SDI countries and territories increased slightly over the past 28 years, in contrast, the ASDR decreased slightly, with an EAPC of -1.21% (95% CI -1.29% to -1.12%, P<0.01). Both the DALY and age-standardized DALY rates in the high-middle-SDI countries decreased sharply from 1990 to 2017 and with an the EAPC of -1.72% (95% CI -1.85% to -1.59%, P<0.01) (Table 1 and Figure 1E–1H).

Sex patterns

In the current study, the ASPRs of leukemia per 100,000 population were 36.33 (95% UI 32.14 to 39.18) in males and 28.75 (95% UI 24.65 to 31.83) in females in 2017. There was a moderate decline in the ASPR in females, whereas the rate was significantly increased in males during the same period. At the global level, the ASRs in high-SDI, and high-middle-SDI countries and territories were mostly higher in males than in females. In addition, there were no obvious differences in the ASRs between male and female in middle-SDI, low-middle-SDI, and low-SDI countries and territories (Figure 3). The ASPR trend increased yearly in middle-high-SDI countries and territories, peaking in 2016 in both males and females (Figure 3B). Among the ASRs observed in the past 28 years, only the ASPR in males had an increased EAPC (0.43% (95% CI 0.34% to 0.53%, P<0.01)) (Table 1). Statistics were calculated on the basis of the five types of leukemia in males and females. Among the leukemia types, acute myeloid leukemia (AML) was the leading contributor to the ASIR, ASDR, and the age-standardized DALY rate. Regarding the ASPR of leukemia in 2017, chronic lymphocytic leukemia (CLL) (8.28 (95% UI 7.66 to 8.95)) was the second leading contributor in males, whereas acute lymphocytic leukemia (ALL) (6.65 (95%UI 5.17 to 7.90)) was the second leading cause in female. chronic myeloid leukemia (CML) accounted for the smallest proportion of all ASRs (Figure 4A–4D).

Age pattern

The trend and distribution of leukemia in 2017 was generally similar to that in 1990 by age group. The total incidence rates and prevalence rates in 2017 were slightly higher than those in 1990, while mortality and DALY rates remained stable between 1990 and 2017. The 95 and older age group had the highest incidence rate and mortality rate per 100,000 population both in 1990 and 2017, and both rates increased with age. For the incidence rate in the 95 and older age group, CLL (34.73 (95% UI 31.51 to 38.17)) accounted for the largest proportion in 2017. For the mortality rate in the 95 and older age group, other leukemia types (30.87 (95% UI 29.46 to 32.49)) accounted for the largest proportion. ALL accounted for the smallest proportion of both rates in the 95 and older age group, with an incidence rate of 1.50 (95% UI 1.42 to 1.58) and a mortality rate of 1.98 (95% UI 1.87 to 2.03) in 2017. The prevalence rate of ALL was the highest in infants and young children in 2017, especially in the group aged 1-4 years, with a prevalence rate of 32.31 (95% UI 25.14 to 38.82) per 100,000 population. CLL was the leading cause of leukemia in elderly people in both 1990 and 2017. The peak DALY rate of leukemia in 2017 occurred in the group aged 80-84 (409.53 (95% UI 384.16 to 429.09)) per 100,000 population, AML had a DALY rate of 115.08 (95% UI 106.36 to 120.29), ranking second to only other leukemia types (160.17 (95% UI 147.68 to 172.93)) (Figure 4E–4H).

Correlation between the burden of leukemia and the sociodemographic index

Overall, a positive association was observed between the ASIR and SDI (Supplementary Figure 4A), as well as the ASPR and SDI (Figure 5A) for all Global Burden of Disease (GBD) regions from 1990 to 2017. At the global level, the ASIR estimates of leukemia were higher than expected in Australasia, East Asia, North Africa and the Middle East, Oceania, Southeast Asia, and Western Europe based on the SDI during 1990-2017. Moreover, globally, the ASPR estimates in only Andean Latin America, Australasia, and East Asia, were higher than expected. The ASDRs of the GBD regions increased slightly with increasing SDIs (Supplementary Figure 4B). A significant positive association between the age-standardized YLD due to leukemia and the SDI (Supplementary Figure 4C) was observed, and the middle-SDI GBD regions had the highest age-standardized DALY rates per 100,000 population (Figure 5B).

The same correlation was observed in the correlation analysis of the burden of leukemia in 2017 and the SDIs of 195 GBD countries and territories (Figure 6A and Supplementary Figure 5). The high burden of leukemia was not limited to developing countries such as China, Syria, Afghanistan, and Honduras. Developed countries, such as–the United Kingdom, Denmark, Slovakia, and Switzerland–had a much higher leukemia burden than expected.

We also analyzed the EAPCs of 195 countries and territories by SDI in 2017. We observed a statistically significant correlation between the EAPC in the ASPR and the SDI (R=0.34, P<0.01). In addition, a negative correlation between the change in the ASDR and SDI (R=-0.41, P<0.01), was found; this correlation was also observed for the DALYs trend (R=-0.51, P<0.01) in 2017. There was no correlation between the EAPC in the ASIR and SDI (Figure 5C).

Risk factors contributing to the leukemia burden

Tobacco use, smoking, and behavioral risks factors were the three largest contributors to DALYs globally, especially in high-SDI countries and territories in 1990 (Figure 6B). Leukemia-related DALYs attributable to tobacco use and smoking varied globally by sex in 2017 (Figure 6C). In 1990, 34.34% (95% UI 24.02% to 44.08%) and 11.97% (95% UI 8.80% to 17.01%) of leukemia cases were attributable to tobacco use and smoking in males and females, respectively, but the leading risk factor for leukemia in females changed in 2017. Tobacco use and smoking accounted for 35.41% (95% UI 24.26% to 47.38%) of global leukemia DALYs in males in 2017, while the proportion decreased to 10.22% (95% UI 3.07% to 13.97%) in females. Metabolic risks factors and high body mass index contributed to the increase in leukemia in females in 2017 (11.55% (95% UI 5.34% to 18.97%)), overtaking tobacco use- and smoking-attributable leukemia rates in females (Supplementary Figure 6A–6D). Similarly, deaths attributable to risk factors including tobacco use, smoking, behavioral risk factors, metabolic risk factors and high body mass index had the same DALYs and risk factors patterns (Supplementary Figure 6E, 6F).

Data source

Data on the incidence, prevalence, mortality, DALYs, and years lived with disability (YLDs) of leukemia from 1990 to 2017 were obtained from the Global Health Data Exchange (GHDx) query tool (http://ghdx.healthdata.org/gbd-results-tool), which is a catalog of global health and demographic data from the GBD study 2017. The GBD study 2017, conducted by the Institute of Health Metrics and Evaluation (IHME), is the largest and most complete study to date, providing data on epidemiological characteristics and worldwide trends. Twenty-one regions, 7 super-regions and 195 countries and territories were included in the GBD study 2017.

Case definition

The subtypes of leukemia–ALL, AML, CLL, and CML–were identified based on the International Classification of Diseases and Injuries-10^th edition (ICD-10) diagnostic codes (Supplementary Table 1). The current study employed the GBD study 2017 definition of the prevalence of leukemia: a diagnosis and primary therapy phase of 5 months, a metastatic phase of 43.67 months, and a terminal phase of 1 month. All the phases were presented with their respective disability weights (Supplementary Table 2) [25, 26]. In addition, survivals beyond ten years was considered cured. A systematic review of the incidence and prevalence of leukemia was performed for 1980-2015 for the GBD study 2016 and updated for the GBD study 2017 [26]. The standardized methods of the GBD study 2017 have been reported elsewhere [27]. The prevalence and DALYs of leukemia were estimated for 195 countries and territories using DisMod-MR 2.1, a Bayesian meta-regression tool [26]. All estimates are presented as counts, computed from the means of 1000 draws, and 95% uncertainty intervals (95% UI) were determined using 97.5% and 2.5% of the distribution of draws. To compute YLDs for a particular health outcome in a given population, the number of people living with that outcome is multiplied by a disability weight that represents the magnitude of health loss associated with the outcome of interest [27]. Years of life lost (YLLs) due to leukemia were calculated using standard global life expectancy values and the number of deaths according to age [27]. Leukemia DALYs were computed as the sum of YLDs and YLLs.

Sociodemographic index

The SDI is a composite indicator of development status and was obtained from the GBD study. It was calculated from a geometric mean ranging from 0 to 1, which accounts for average educational attainment in the population older than 15 years (EDU15+), total fertility rate in those under 25 years (TFU25), and lag-distributed income (LDI) per capita [28], with SDI scales to confirm the minima and maxima, which are listed in Supplementary Table 3. The index scores for calculating the SDIs were computed as follows: I_Cly= (C_ly- C_low)/(C_high- C_low), where I_Cly is the index value for covariate C, location l, and year y. In addition, the index value for TFU25 was calculated as (1-I_TFU25ly); a lower TFU25 corresponds to a higher level of development. Countries and territories were classified as regions with low, low-middle, middle, high-middle, and high SDIs.

Statistical analyses

The ASR per 100,000 population is equal to the sum of the product of the specific age ratio (a_i) in age group i and the number or weight (w_i) of the selected reference standard population group i divided by the sum of the number or weight of the standard population. ASRs were calculated on the basis of the following formula:

$\text{ASR}=\frac{{{\displaystyle \sum }}_{i=1}^{A}aiwi}{{{\displaystyle \sum }}_{i=1}^{A}wi}\times 100,000$

The EAPC was used to quantify the trends of the ASRs over a specified interval, which were computed using a generalized linear model with a Gaussian distribution [29–31]. A regression line was fitted to the natural logarithm of the rates, i.e., y =α+βx+ε, where x = year and y = ln(rate), from which 95% confidence intervals were obtained; the EAPC was calculated as 100 × (e^β - 1). A positive EAPC indicated an upward ASR trend, whereas a negative EAPC indicated a downward trend. Spearman’s rank order correlation was used to measure the associations between ASRs and SDIs, and the Pearson correlation coefficient was used to quantify the correlation between EAPCs and SDI from 1990 to 2017. A P value of less than 0.05 was regarded as statistically significant. All statistical analyses were performed using the R program (Version 3.6.3).

Availability of data and materials

All data and materials supporting the conclusions of this study have been included within the article.