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Xu et al. J Transl Genet Genom 2021;5:218-39 https://dx.doi.org/10.20517/jtgg.2021.20 Page 222

Among API regional groups, East Asians have a significantly higher IR of childhood ALL compared to
[93]
Southeast Asians (IRR = 1.59), and Oceanians have the highest IR .
Among AYAs aged 15-39 years (age range defined by the National Cancer Institute), the overall ALL AAIR
was 0.98 (95%CI: 0.96-1.01) per 100,000 during 2000-2016, with the highest incidence being observed in
Hispanics/Latinos [AAIR = 1.63 (95%CI: 1.56-1.70)], followed by AI/ANs [AAIR = 1.16 (95%CI: 0.86-1.52)],
NHWs [AAIR = 0.79 (95%CI: 0.76-0.83)], APIs [AAIR = 0.78 (95%CI: 0.70, 0.86)], and Blacks [AAIR = 0.53
(95%CI: 0.47, 0.59)] [Figure 1]. A similar trend has been found in B-ALL specifically, with the highest
[66]
[94]
incidence seen in Hispanics/Latinos and the lowest in Blacks .
Among older adults, ALL incidence again predominates among Hispanics/Latinos . For those aged 40 or
[5]
older, Hispanics/Latinos had the highest AAIR [AAIR = 1.76 (95%CI: 1.67-1.86)], followed by AI/ANs
[AAIR = 1.17 (95%CI: 0.87-1.54)], NHWs [AAIR = 0.97 (95%CI: 0.94-1.00)], APIs [AAIR = 0.85 (95%CI:
[66]
0.78-0.93)], and Blacks [AAIR = 0.77 (95%CI: 0.70-0.84)] [Figure 1].

Furthermore, Philadelphia chromosome-like (Ph-like) ALL [patients with a similar gene expression pattern
as those with t(9;22), BCR-ABL1 translocations, i.e., Ph+], a subtype of B-ALL associated with poor
outcomes , is more common in AYAs (19%-27%) and older adults (20%) than in children (10%) [96-99] . In
[95]
addition, patients with Ph-like ALL or with its subtype carrying CRLF2 rearrangement (also associated with
poor outcomes) are more likely to be Hispanics/Latinos compared to other races/ethnicities (68% in Ph-
[99]
like ALL and 85% in Ph-like ALL with CRLF2 rearrangement) .
[99]
Intriguingly, a higher percentage of residents born in a foreign country at the county level contributes to a
higher incidence of ALL among both NHWs and Blacks, but was contradictorily associated with a lower
incidence of ALL among Hispanics/Latinos . For United States-based API children, ALL IRs were similar
[66]
[93]
to rates seen in originating countries . The inverse association between percent foreign-born and the
incidence of ALL in Hispanics/Latinos represents an example of the “Hispanic paradox” [100,101] , which refers
to the observation that foreign-born Hispanics/Latinos have better health outcomes when compared to
United States-born Hispanics/Latinos.

Incidence of ALL is rising fastest in Hispanics/Latinos
During 1992-2013, the incidence of ALL increased significantly by approximately 2% per year for
Hispanic/Latino children diagnosed from age 10-14 years (APC = 2.09), and by 3% for those 15-19 years of
age (APC = 2.67), while no significant increases were observed in NHW, Black, or Asian children in the
[64]
same age groups . In the United States Cancer Statistics database, the IR of ALL in both overall children
and Hispanic children aged below 20 years increased significantly during 2001-2008, with the largest
increase being observed in Hispanic/Latino children (APC = 2.5), and which remained stable during 2008-
2014 .
[65]
Despite of the relatively low AAIR of ALL compared to other age groups, AYA had the greatest increase of
[66]
ALL AAIR during 2000-2016 [overall APC = 1.56 (95%CI: 1.03-2.09)] [Figure 1]. Hispanics/Latinos had
significant increase of AAIR across all age groups [APC = 1.18 (95%CI: 0.76-1.60)], with the greatest
[66]
increase found in AYAs [APC = 2.02 (95%CI: 1.17-2.88)] . Across all age groups, AYA is the only group in
which AI/ANs had a significant increase of AAIR [APC = 9.79 (95%CI: 5.65-14.09)] . Given the small
[66]
population size of AI/ANs, the substantial interregional differences of incidence rates and misclassification
of AI/ANs in central registries that were observed in SEER data , a note of caution should be offered in
[102]
interpreting rates and trends for the AI/AN population. The AAIR of ALL also increased significantly