Abstract
Hispanic children with acute lymphoblastic leukemia (ALL) have lower 6-mercaptopurine (6MP) adherence and greater hazard of relapse compared with non-Hispanic White children. We examined the association between Spanish language and 6MP adherence, and hazard of relapse. 6MP adherence was measured electronically over a 6-month period. Participants were grouped by the language of demographic questionnaire completion: Non-Hispanic White-English Speaking (ES, n = 159), Hispanic-Spanish Speaking (Hispanic-SS, n = 59), and Hispanic-ES (n = 109). Hispanic-ES had significantly lower fitted median 6MP adherence compared with non-Hispanic White-ES participants (88.3%, 95% CI = 84.7% to 91.2% vs 95.0%, 95% CI = 93.6% to 96.2%, P < .001). There was no difference in fitted median 6MP adherence between Hispanic-ES and Hispanic-SS participants (88.3%, 95% CI = 84.1% to 91.5% vs 88.3%, 95% CI = 84.7% to 91.2%, P = .9) or adjusted hazard of relapse for Hispanic-SS participants (HR = 0.9, 95%CI = 0.3 to 2.4, P = .8). Spanish language use among Hispanic patients with ALL is not associated with lower 6MP adherence or greater relapse risk. Factors related to Hispanic ethnicity, apart from language, appear to influence adherence.
Compared with non-Hispanic White children, Hispanic children with acute lymphoblastic leukemia (ALL) have lower 6-mercaptopurine (6MP) adherence and greater hazard of relapse (1). Causal mechanisms of lower 6MP adherence among Hispanic children with ALL remain understudied. More than 26 million Americans use languages other than English (LOE) at home (2). Language barriers could result in poor understanding of medication importance and/or administration instructions and promote nonadherence. Among other diseases, the association between LOE use and medication adherence has shown conflicting findings (3-5). Whether LOE use among Hispanic patients (ie, Spanish) with ALL is associated with lower 6MP adherence remains unknown. We examined the association between Spanish language and 6MP adherence, as well as hazard of relapse, among Hispanic and non-Hispanic White children with ALL.
Data were collected from the Children’s Oncology Group (COG) study AALL03N1 (primary aim: 6MP adherence and relapse risk; study eligibility has been previously published (1)). Participating sites obtained institutional review board approval. Patients (if ≥18 years at enrollment) and/or parents provided informed consent before participation. COG-AALL03N1 enrolled 470 patients who participated in 6MP adherence monitoring. Among those who participated in 6MP adherence monitoring and returned a demographic questionnaire, 327 self-identified as Hispanic (n = 168) or non-Hispanic White (n = 159); rates of questionnaire completion were 98.2% among Hispanic participants and 100% among non-Hispanic White participants. Participants completed a demographic questionnaire in English or Spanish at study enrollment and reported parental education, annual household income, and household structure. Questionnaires were completed by parents except for 8 (4.8%) Hispanic and 3 (1.9%) non-Hispanic White patients who were greater than or equal to 18 years at study entry and completed the questionnaire themselves. Sites reported disease characteristics and clinical outcomes for 10 years after enrollment. Adherence was measured over 6 months using an electronic monitoring device (TrackCap Medication Events Monitoring Systems [MEMS]; Aardex; Sion, Switzerland) and calculated as ratio of days of MEMS cap openings to days prescribed. Participants were placed into 3 groups based on self-reported race and ethnicity and their preference for completing the study questionnaires as non-Hispanic White-English Speaking (ES), Hispanic-Spanish Speaking (Hispanic-SS), and Hispanic-ES. Generalized linear regression models compared fitted median 6MP adherence rates between groups adjusting for age at study entry, sex, risk group, blast cytogenetics, study month, parental education, household income, household structure, and 6MP dose intensity (=prescribed dose/protocol dose). Proportional sub-distribution hazard regression models determined the hazard of relapse by language, adjusting for age at study entry, sex, blast cytogenetics, parental education, household income, 6MP adherence, and time from start of maintenance, treating death as competing risk. Analyses were performed using SAS v9.4 (SAS Institute, Inc); 2-sided tests with P less than .05 were considered significant.
Among Hispanic participants, 109 (64.9%) completed the questionnaire in English and 59 (35.1%) in Spanish. Compared with Hispanic-ES participants, Hispanic-SS participants were less likely to live in a single-mother household and more likely to report parental education less than or equal to high school (Table 1). Median 6MP dose intensity was comparable among the 3 groups. Hispanic-ES participants had significantly lower fitted median 6MP adherence compared with non-Hispanic White-ES participants (88.3%, 95% confidence interval [CI] = 84.7% to 91.2% vs 95.0%, 95% CI = 93.6% to 96.2%, P < .001) (Table 2). However, there was no difference in fitted median 6MP adherence between Hispanic-ES and Hispanic-SS participants (88.3%, 95% CI = 84.1% to 91.5% vs 88.3%, 95% CI = 84.7% to 91.2%, P = .9). Compared with Hispanic-ES participants, the adjusted hazard of relapse was not different for Hispanic-SS participants (HR = 0.9, 95% CI = 0.3 to 2.4, P = .8).
Table 1.
Demographic and clinical characteristics of eligible participants with ALL
| Characteristic | Entire cohort (n = 327) | Non-Hispanic White (n = 159) | Hispanic-SS (n = 59) | Hispanic-ES (n = 109) |
|---|---|---|---|---|
| Age at diagnosis in years | ||||
| Median (range) | 4 (1,19) | 5 (1,19) | 4 (1,16) | 4 (1,18) |
| Age at study entry in years | ||||
| Median (range) | 6 (2,20) | 6 (2,20) | 5 (2,17) | 6 (2,20) |
| Length of follow up from study entry in years | ||||
| Median (range) | 7.9 (0.2,10.1) | 7.9 (0.2,10.1) | 8.1 (0.9,9.8) | 7.9 (0.2,9.5) |
| Sex, n (%) | ||||
| Male | 217 (66.4) | 104 (65.4) | 43 (72.9) | 70 (64.2) |
| ALL subtype, n (%) | ||||
| B-cell | 299 (91.4) | 142 (89.3) | 54 (91.5) | 103 (94.5) |
| NCI Risk Group, n (%) | ||||
| High-Risk | 125 (38.3) | 64 (40.3) | 18 (30.5) | 43 (39.8) |
| Cytogenetics, n (%) | ||||
| Favorable | 134 (43.7) | 64 (42.4) | 28 (49.1) | 42 (42.4) |
| Unfavorable | 15 (4.9) | 9 (6.0) | 1 (1.8) | 5 (5.1) |
| Household structure, n (%) | ||||
| Single mother | 36 (11.1) | 10 (6.3) | 5 (8.8) | 21 (19.3) |
| Parental education, n (%) | ||||
| Paternal education ≤HS | 161 (50.5) | 43 (27.0) | 48 (84.2) | 70 (68.0) |
| Maternal education ≤HS | 141 (43.7) | 32 (20.1) | 48 (82.8) | 61 (57.6) |
| Annual household income, n (%) | ||||
| ≤$20 000 | 84 (25.7) | 10 (6.3) | 29 (49.2) | 45 (41.3) |
| Dose intensity | ||||
| Median (range) | 86.9 (6.0-161.5) | 85.7 (6.0-129.6) | 85.8 (28.6-161.5) | 88.2 (34.4-145.4) |
ALL = acute lymphoblastic leukemia; NCI = National Cancer Institute (standard risk: age ≤9.99 years and white blood cell count <50 000 cells/µL at ALL diagnosis; high risk if otherwise); HS = high school; SS = Spanish speaking; ES = English Speaking
Favorable cytogenetics included t(12; 21); hyperdiploidy; trisomy 4 and 10; or trisomy 4, 10, and 17. Unfavorable cytogenetics included t(9; 22), t(4; 11), hypodiploidy, or extreme hypodiploidy.
Table 2.
Effect of language on adherence among eligible participants
| Variables | Estimate (SE) | Fitted median adherence (95% CI) | P |
|---|---|---|---|
| Race, ethnicity, and language | |||
| Hispanic-ES | Reference | 88.3 (84.7 to 91.2) | – |
| Non-Hispanic White | 0.9 (0.2) | 95.0 (93.6 to 96.2) | <.001 |
| Hispanic-SS | 0.0 (0.2) | 88.2 (84.1 to 91.5) | .9 |
Model adjusts for time from start of maintenance, age at diagnosis, sex, NCI risk group, blast cytogenetics, study month, household structure, parental education, household income, and dose intensity. Estimate refers to the coefficient from the generalized linear regression model. SE = standard error; CI = confidence interval; SS = Spanish-speaking; ES = English-speaking; NCI = National Cancer Institute.
We show that Spanish language use among Hispanic patients with ALL is not associated with lower 6MP adherence or greater relapse risk. Additionally, lower 6MP adherence among Hispanic-ES patients with ALL compared with non-Hispanic White patients indicates that factors related to Hispanic ethnicity, apart from language, influence adherence. Lower 6MP adherence is a modifiable risk factor that could partly eliminate survival disparities in Hispanic children compared with non-Hispanic White children with ALL (6). Limitations of this study include its retrospective design precluding the prospective assessment of language proficiency and the assumption that preferred reading language of participants represents their preferred communication language. Additionally, participants facing significant barriers to language-appropriate care may choose to not enroll in studies, potentially introducing selection bias. Finally, information on the use of medical interpreters during clinic visits was not available and may limit interpretation of these findings. Although this analysis was limited by classifying groups by the language in which families opted to complete the questionnaire rather than direct assessment of language, this is the first study to evaluate the association of language and 6MP adherence among children with ALL. This study highlights the need to further investigate cultural barriers, social determinants of health, such as health literacy, and acculturation in Hispanic children with ALL to inform culturally appropriate interventions and improve 6MP adherence.
Acknowledgments
Role of the Funder/Sponsor: The funder had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; or decision to submit the manuscript for publication.
Disclaimer: The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
Contributor Information
Joanna Robles, Section of Pediatric Hematology Oncology, Department of Pediatrics, Wake Forest University School of Medicine, Winston Salem, NC, USA; Atrium Health Wake Forest Baptist Comprehensive Cancer Center, Winston Salem, NC, USA.
Yanjun Chen, Institute for Cancer Outcomes and Survivorship, University of Alabama at Birmingham, Birmingham, AL, USA.
Lindsey Hageman, Institute for Cancer Outcomes and Survivorship, University of Alabama at Birmingham, Birmingham, AL, USA.
Paula Aristizabal, Division of Pediatric Hematology/Oncology, Department of Pediatrics, University of California San Diego/Rady Children’s Hospital, San Diego, CA, USA; Population Sciences, Disparities and Community Engagement, Moores Cancer Center, La Jolla, CA, USA; Dissemination and Implementation Science Center, Altman Clinical and Translational Research Institute, La Jolla, CA, USA.
Wendy Landier, Institute for Cancer Outcomes and Survivorship, University of Alabama at Birmingham, Birmingham, AL, USA; Division of Pediatric Hematology/Oncology, Department of Pediatrics, University of Alabama at Birmingham, Birmingham, AL, USA.
Smita Bhatia, Institute for Cancer Outcomes and Survivorship, University of Alabama at Birmingham, Birmingham, AL, USA; Division of Pediatric Hematology/Oncology, Department of Pediatrics, University of Alabama at Birmingham, Birmingham, AL, USA.
Aman Wadhwa, Institute for Cancer Outcomes and Survivorship, University of Alabama at Birmingham, Birmingham, AL, USA; Division of Pediatric Hematology/Oncology, Department of Pediatrics, University of Alabama at Birmingham, Birmingham, AL, USA.
Data availability
Data are available upon reasonable request to the author, Smita Bhatia (smitabhatia@uabmc.edu).
Author contributions
Joanna Robles, MD (Conceptualization; Funding acquisition; Investigation; Methodology; Project administration; Writing—original draft; Writing—review & editing), Yanjun Chen, MS (Data curation; Formal analysis; Investigation; Project administration; Resources; Writing—review & editing), Lindsey Hageman, MPH (Data curation; Investigation; Methodology; Project administration; Resources; Writing—review & editing), Paula Aristizabal, MD, MAS (Conceptualization; Writing—review & editing), Wendy Landier, PhD, CRNP (Investigation; Methodology; Project administration; Resources; Writing—review & editing), Smita Bhatia, MD MPH (Conceptualization; Data curation; Funding acquisition; Investigation; Methodology; Project administration; Resources; Supervision; Writing—original draft; Writing—review & editing), Aman Wadhwa, MD, MSPH (Conceptualization; Data curation; Formal analysis; Investigation; Methodology; Project administration; Resources; Supervision; Writing—original draft; Writing—review & editing).
Funding
The authors acknowledge support from National Clinical Trials Network (NCTN) Operations Center grant (U10CA180886), NCTN Statistics & Data Center grant (U10CA180899), St Baldrick’s Foundation, and National Cancer Institute Community Oncology Research Program (NCORP) grant (UG1CA189955) to the Children’s Oncology Group, as well as a National Institutes of Health/National Cancer Institute grant (R01 CA096670) to S.B. This project was also supported by funds from The Children’s Cancer Research Fund to J.R.
Conflicts of interest
The authors do not have any direct or indirect commercial financial incentive associated with publishing this article.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
Data are available upon reasonable request to the author, Smita Bhatia (smitabhatia@uabmc.edu).