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Page 231 Xu et al. J Transl Genet Genom 2021;5:218-39 https://dx.doi.org/10.20517/jtgg.2021.20

Access to care
Previous studies have shown that older age was associated with less treatment adherence , and that
[80]
compliance with therapy was more problematic for AYAs than for other age groups [181-183] ; however, the
heterogeneity by race/ethnicity has been investigated mostly in childhood ALL patients. Lower exposure to
mercaptopurine increases the risk of relapse in ALL, and thus the increased risk of relapse in
Hispanic/Latino children with ALL compared with NHW children with ALL may in part result from a
lower compliance to oral mercaptopurine therapy . In a 6-month adherence monitoring program of 327
[184]
patients with ALL, Hispanic/Latino children had a significantly lower level of adherence along with lower
SES compared to NHW children . In another 5-month follow-up study among children with ALL from
[177]
COG, adherence rates for oral 6-mercaptopurine were significantly lower in Blacks (87%) and Asian
Americans (90%), as compared to NHWs (95%), after adjusting for SES . These suggest that compliance
[185]
to therapy could be explained by factors other than SES. In addition, the type of insurance payer is a
significant predictor of adherence among ALL patients. It has been found that ALL patients with
commercial insurance payers had significantly higher levels of adherence compared to those with
[186]
Medicaid . Compared to other age groups, the AYA group is less likely to have insurance, with around
40% of individuals between 19 and 29 years old being uninsured . Hispanic/Latino and Black adult
[187]
patients with cancer are more likely to be uninsured or Medicaid-insured than NHW adult patients . A
[180]
pediatric cancer study has also demonstrated that Hispanic/Latino patients were less likely to have
insurance . Notably, despite that Black children with ALL were significantly more likely to have high-risk
[188]
prognostic profiles compared to NHW children, it has been found that with equal access to effective
antileukemic therapy, Blacks and NHWs had the same high rate of cure .
[189]

Recruitment to clinical trials
In addition to the elevated incidence of Ph-like ALL in AYA ALL patients [96-99] , potential factors that
contribute to the AYA “survival cliff” also include the transition from pediatric to adult treatment
[190]
[110]
regimens and the low recruitment rate of AYA patients into clinical trials . For instance, a drop off in
clinical trial accruals for ALL has been identified during age 16-24, where the estimated treatment trial
accrual proportion decreased dramatically from 50% at age 16 to below 10% at age 24 during 2000-2014 .
[190]
This pattern strongly suggests that the AYA survival cliff could be in fact largely due to an “accrual cliff”, as
survival has been found to strongly correlate with trial accrual . Moreover, there was a lack of
[190]
improvement in ALL survival in patients aged 20-29 years since 1989 (APC = 0.33, P = 0.39), corresponding
to the negligible increase of trial accrual in AYAs during 2000-2015 . In addition to AYAs, elderly ALL
[190]
patients are rarely eligible for clinical trials and are underrepresented in trials of new cancer therapy [191,192] ,
and the underrepresentation in clinical trials for cancer therapies has been found to underlie the poor
outcomes of elderly patients . In addition to age disparities, Black AYA cancer patients are less likely to be
[192]
[193]
enrolled on a clinical trial compared to NHW AYAs , and NHWs continue to comprise the majority of
participants in these trials .
[194]
CONCLUSIONS AND FUTURE DIRECTIONS
In this review, we described racial/ethnic disparities in ALL risk and survival; evaluated how these vary
across the age spectrum; and examined the potential causes of these disparities, including genetic and non-
genetic risk factors. Genetic risk factors certainly play a significant role in contributing to these disparities,
as several ALL risk loci are associated with genetic ancestry, and have demonstrated different risk allele
frequencies and/or effect sizes across population groups. In particular, multiple studies have shown that Ph-
like ALL is associated with poor survival in both children and adults, and the risk of Ph-like ALL is
associated with specific GATA3 risk alleles that occur more frequently in Hispanics/Latinos with elevated
Indigenous American ancestry. A variety of genomic aberrations have been discovered underlying Ph-like
ALL and are likely to be drivers of leukemogenesis , which offers a great opportunity for precision
[195]