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\begin{document}

\title{ORAL MERCAPTOPURINE ADHERENCE IN PEDIATRIC ALL: A SURVEY STUDY FROM THE
DFCI ALL CONSORTIUM}



\author[1]{Justine Kahn}%
\author[2]{Maneka Puligandla}%
\author[3]{Kristen Stevenson}%
\author[4]{Peter Cole}%
\author[5]{Jennifer Welch}%
\author[6]{Melissa Beauchemin}%
\author[7]{Elizabeth Gage-Bouchard}%
\author[2]{Lewis Silverman}%
\author[7]{Kara Kelly}%
\author[3]{Kira Bona}%
\affil[1]{Columbia University Medical Center}%
\affil[2]{Dana Farber Cancer Institute}%
\affil[3]{Dana-Farber Cancer Institute}%
\affil[4]{Rutgers The State University of New Jersey}%
\affil[5]{Hasbro Children's Hospital}%
\affil[6]{Columbia University Medical Centre}%
\affil[7]{Roswell Park Comprehensive Cancer Center}%


\vspace{-1em}



  
  \date{June 14, 2024}


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\selectlanguage{english}
\begin{abstract}
Poor adherence to 6-mercaptopurine during acute lymphoblastic leukemia
(ALL) therapy increases relapse risk. Clinically-significant
non-adherence has been documented in up to 30\% of children treated for
ALL on Children's Oncology Group trials. Whether non-adherence rates
vary across regimens with different chemotherapy schedules and modes of
administration is not known. In a cross-sectional survey study of N= 61
children treated on, or as per Dana-Farber Cancer Institute (DFCI) ALL
Consortium Protocol 11-001, 25\% (95\% CI 14 -- 37\%) of respondents
self-reported non-adherence to 6MP, suggesting that the frequency of
non-adherence may be similar across different Consortia regimens.%
\end{abstract}%



\sloppy


\textbf{ABSTRACT:} Poor adherence to 6-mercaptopurine during acute
lymphoblastic leukemia (ALL) therapy increases relapse risk.
Clinically-significant non-adherence has been documented in up to 30\%
of children treated for ALL on Children's Oncology Group trials. Whether
non-adherence rates vary across regimens with different chemotherapy
schedules and modes of administration is not known. In a cross-sectional
survey study of N= 61 children treated on, or as per Dana-Farber Cancer
Institute (DFCI) ALL Consortium Protocol 11-001, 25\% (95\% CI 14 --
37\%) of respondents self-reported non-adherence to 6MP, suggesting that
the frequency of non-adherence may be similar across different Consortia
regimens.



\textbf{INTRODUCTION}

Successful treatment of pediatric acute lymphoblastic leukemia (ALL)
requires at least two-years of risk-directed therapy built on a backbone
of oral chemotherapy, including 6-mercaptopurine (6MP) and
dexamethasone. Studies from the Children's Oncology Group (COG)
demonstrated that less than 90\% adherence to 6MP during maintenance
therapy was associated with up to a 3.9-fold increased relapse
risk.\textsuperscript{1} Non-adherence in these studies was associated
with lack of routine surrounding medication taking, patient
race/ethnicity and age, household structure, and parent educational
attainment.\textsuperscript{1} Little is known about 6MP adherence rates
in the context of non-COG ALL treatment regimens---where different
treatment schedules and modes of chemotherapy delivery (e.g. oral versus
intravenous {[}IV{]} administration of chemotherapy agents) may impact
frequency and reasons for non-adherence.

Compared to the continuous daily 6MP, oral weekly methotrexate and
repeating 4-week cycles in COG ALL trials, Dana-Farber Cancer Institute
(DFCI) ALL Consortium protocols utilize 14-day pulses of 6MP with weekly
IV methotrexate throughout maintenance in repeating 3-week
cycles.\textsuperscript{2} This chemotherapy delivery approach requires
more frequent contact between families and healthcare providers and
reduces the number of oral chemotherapy agents. We explored whether the
``higher-touch'' of every 3-week clinic visits for cycle initiation
along with use of IV methotrexate--necessitating weekly clinic visits or
visiting nurse administration---might reduce the frequency of 6MP
non-adherence on the DFCI regimen as compared to published COG
data.\textsuperscript{3} Specifically, we aimed to explore the
prevalence of parent-reported 6MP non-adherence in the context of DFCI
ALL Consortium-based therapy utilizing a cross-sectional survey, and to
identify whether sociodemographic factors, medication-taking logistics
or chemotherapy comprehension impacted adherence rates in a DFCI cohort.

\textbf{Results}

\textbf{PATIENTS and METHODS}

\emph{Study Context:} The DFCI ALL Consortium conducts Phase 3 clinical
trials for ALL at 8 U.S. and Canadian centers. DFCI Protocol 11-001
enrolled children from 2012 to 2015, and treatment as per DFCI 11-001
became the standard of care for patients at participating Consortium
sites following trial closure after accrual. DFCI 11-001 included a
two-year treatment course with a 70-week Continuation (maintenance)
phase. Each 3-week cycle included day 1 vincristine (IV), days 1 -- 5
dexamethasone (oral), days 1, 8, 15 methotrexate (IV), and days 1-14 6MP
(oral). Parents were instructed to administer 6MP at bedtime, on an
empty stomach, at least two hours before, and one hour after food or
milk.

\emph{Patients:} Eligible participants were English or Spanish speaking
caregivers of children ages 1-18 years receiving Continuation therapy on
or as per DFCI 11-001 between February 2015 and March 2017 at one of
four participating Consortium sites (Montefiore Medical Center, Bronx,
NY, Columbia University Irving Medical Center, New York, NY, DFCI,
Boston, MA, and Hasbro Children's Hospital of Rhode Island, Providence,
RI). Informed consent/assent was obtained for all subjects and the study
was approved by the Institutional Review Board at participating sites.

\emph{Surveys:} Parent/guardians completed a single time-point,
paper-pencil survey during a regularly scheduled clinic visit on Day 1
of a 3-week Continuation cycle. The survey included sociodemographic
variables (patient/parent age, race, ethnicity, country of origin,
family structure, education for each parent/guardian, household income,
food insecurity, and marital status)\textsuperscript{4} as well as 33
dichotomous and multiple-choice questions related to 6MP comprehension,
administration, and adherence adapted with permission from Bhatia et
al.\textsuperscript{4} Low parental education was defined as having
completed some high-school or less vs. high school graduate or
more.\textsuperscript{5} Adherence survey questions inquired about
medication-taking routines, daily administration challenges, and
perceived risks associated with missing 6MP. Free-text questions asked
whether more resources or reminders would be helpful to improve
adherence.

\emph{Non-adherence:} Patients were defined as 6MP non-adherent using
two survey metrics of missed doses. These included: (1) a response of
\textless{}14 days to the question ``\emph{During the past 3 weeks, how
many days did your child take 6MP?} '' and (2) endorsement of missed
doses during a \emph{prior} \emph{cycle,} or other changes to prescribed
chemotherapy without instruction from a medical provider.

\textbf{Statistical Analysis}

Descriptive statistics were generated for all data. Comparison between
two groups (adherent and non-adherent) was performed using two-sided
Wilcoxon rank-sum tests for continuous variables and Fisher exact tests
for categorical variables. 95\% exact binomial confidence intervals were
calculated for the proportion of patients considered adherent and
additional survey questions. P-values \textless{}0.05 were considered
significant

\textbf{RESULTS}

The analytic cohort included 61 families with evaluable self-report
adherence data (Table 1). Fifteen (25\%, {[}95\% CI, 14-37\%{]})
patients met the study definition of 6MP non-adherence. Twenty-five
percent did not have a medication-taking routine. Paternal education
level differed significantly between adherent and non-adherent patients.
Of the group of fathers who completed high school or more 81\% were
adherent compared to only 43\% who did not complete high school
(p=0.045). Five percent of participants endorsed difficulty paying for
their 6MP, however this was not associated with non-adherence.

When asked ``what would happen if your child stopped taking 6MP,'' only
N= 30 (49\% {[}95\% CI, 36-62\%{]}) parents reported ``relapse'' or
``cancer returning.'' The most common reasons for missing 6MP were
related to dosing restrictions around food or falling asleep prior to
bedtime dose administration. Fourteen (23\% {[}95\%CI 13-36\%{]})
parents reported that it was ``not easy'' to follow 6MP administration
guidelines. Across the full cohort, N= 24 (39\% {[}95\% CI 27-53\%{]})
participants suggested that printed calendars would help with adherence
and N=35 (57\% {[}95\% CI, 44-70\%{]}) expressed interest in receiving
educational resources about 6MP

\textbf{DISCUSSION}

Among patients treated with a DFCI ALL Consortium regimen, 25\% {[}95\%
CI, 14\% -- 37\%{]} of caregivers report non-adherence to oral 6MP
during therapy. This rate is strikingly similar to Medication Event
Monitoring System (MEMS)-measured adherence rates from the
COG.\textsuperscript{3,6} Given that self-reported non-adherence has a
sensitivity as low as 53\% but a positive predictive value nearing
95\%,\textsuperscript{7} these data suggest that the frequency of
non-adherence in this cohort is likely an under-estimate of the true
prevalence, and even higher than the non-adherence rates observed in the
COG.

Similar to other studies, non-adherence was associated with parent
education level,\textsuperscript{3} and barriers to adherence included
6MP administration guidelines surrounding food and dairy intake. Only
49\% of parents recognized ``relapse'' or ``cancer returning'' as risks
associated with non-adherence. Studies have demonstrated that patients
who understand the risks and benefits of following medication guidelines
are more likely to adhere to prescribed regimens.\textsuperscript{8} We
previously reported significant variability in approaches to patient
education surrounding oral chemotherapy across DFCI ALL Consortium
sites.\textsuperscript{9} Specifically, providers reported modifying
chemotherapy teaching based on their perceptions of patient
comprehension. Our finding that 25\% of families in the DFCI cohort
reported non-adherence to 6MP suggests that more frequent
patient-provider contact, and individualized oral chemotherapy education
do not mitigate barriers to adherence.

This study was limited by its small sample size, cross-sectional nature,
and self-report adherence measure. Despite limitations, these
exploratory data demonstrate that 1 in 4 families self-report oral 6MP
non-adherence in the context of a chemotherapy regimen reliant on weekly
interactions with the medical team. These findings support the
generalizable nature of published non-adherence data across pediatric
oncology consortia, reinforcing the urgent need for healthcare delivery
intervention development to address non-adherence. Given that parental
education is associated with non-adherence across consortia, future
interventions targeting the efficacy of medical communication may be
warranted. A prospective investigation of oral chemotherapy adherence
using a MEMS-based approach is ongoing in the current DFCI ALL
Consortium trial 16-001 (NCT03020030).

\emph{Acknowledgements:}

We would like to thank Dr. Smita Bhatia for sharing her expertise in
adherence research as well as her permission to adapt her adherence
survey instrument for this study.

JMK is supported by a National Institutes of Health KL2 award from the
Irving Institute for Clinical and Translational Research at Columbia
University Irving Medical Center (NIH-KL2TR001874)

MB is supported by a T32 award from The National Cancer Institute
Training Grant (T32CA094061).

KB is supported by a K07 award from the National Institutes of Health
(K07CA211847).

\emph{References}

1. Bhatia S, Landier W, Hageman L, et al. Systemic Exposure to
Thiopurines and Risk of Relapse in Children With Acute Lymphoblastic
Leukemia: A Children's Oncology Group Study. \emph{JAMA
oncology.}2015;1(3):287-295.

2. Vrooman LM, Blonquist TM, Harris MH, et al. Refining risk
classification in childhood B acute lymphoblastic leukemia: results of
DFCI ALL Consortium Protocol 05-001. \emph{Blood
Adv.}2018;2(12):1449-1458.

3. Bhatia S, Landier W, Hageman L, et al. 6MP adherence in a multiracial
cohort of children with acute lymphoblastic leukemia: a Children's
Oncology Group study. \emph{Blood.} 2014;124(15):2345-2353.

4. Bhatia S, Landier W, Shangguan M, et al. Nonadherence to oral
mercaptopurine and risk of relapse in Hispanic and non-Hispanic white
children with acute lymphoblastic leukemia: a report from the children's
oncology group. \emph{J Clin Oncol.} 2012;30(17):2094-2101.

5. US Census Bureau, American Community Survey. 2016.

6. Landier W, Hageman L, Chen Y, et al. Mercaptopurine Ingestion Habits,
Red Cell Thioguanine Nucleotide Levels, and Relapse Risk in Children
With Acute Lymphoblastic Leukemia: A Report From the Children's Oncology
Group Study AALL03N1. \emph{Journal of clinical oncology : official
journal of the American Society of Clinical
Oncology.}2017;35(15):1730-1736.

7. Landier W, Chen Y, Hageman L, et al. Comparison of self-report and
electronic monitoring of 6MP intake in childhood ALL: a Children's
Oncology Group study. \emph{Blood.} 2017;129(14):1919-1926.

8. Landier W, Hughes CB, Calvillo ER, et al. A grounded theory of the
process of adherence to oral chemotherapy in Hispanic and caucasian
children and adolescents with acute lymphoblastic leukemia. \emph{J
Pediatr Oncol Nurs.} 2011;28(4):203-223.

9. Kahn JM, Athale UH, Clavell LA, et al. How Variable Is Our Delivery
of Information? Approaches to Patient Education About Oral Chemotherapy
in the Pediatric Oncology Clinic. \emph{J Pediatr Health
Care.}2017;31(1):e1-e6.

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