<div>Abstract:</div><div>BACKGROUND: Acute lymphoblastic leukemia (ALL) is the most common
childhood malignancy, with diagnosis preceded by symptoms that may
include fever, weight loss, fatigue, bleeding and bruising. Timely
diagnosis and treatment of ALL may lead to improved outcomes and reduced
morbidity from associated complications including tumor lysis syndrome,
hyperviscosity, and stroke.</div><div>PROCEDURE: We performed a retrospective cohort analysis of 274 pediatric
pre-B cell ALL and lymphoma patients within Montefiore Health System to
determine whether there were factors associated with time from symptom
onset to diagnosis.</div><div>RESULTS: Median time to diagnosis for all patients was 11.5 days
(IQR7.8, 14.3) and was similar between Hispanic, Non-Hispanic Black, and
Non-Hispanic White racial/ethnic groups (10.5 vs 14.0 vs 8.0 days;
p=0.70), and by male and female patients (14 vs 10 days; p=0.08). Those
with Medicaid insurance (n=189) were diagnosed sooner than those with
private or self-pay insurance (n=85) (median of 10 vs 16 days; p=0.05).
Similar findings were demonstrated when evaluating by Medicaid, Private,
and Self-Pay insurance types. English and Other language speakers
experienced fewer median days from symptom onset to diagnosis date
compared to Spanish speakers (11 vs 7 vs 14; p=0.05). Exploratory
analyses suggest that insurance status may impact the time to diagnosis
to a greater degree in Non-Hispanics, while English language and female
sex may represent a greater advantage to Hispanics.</div><div>CONCLUSIONS: This study demonstrates that insurance status and language
preference may impact the time to diagnosis of pediatric ALL. There is
further need to confirm our findings and to study possible causes
driving these disparities.</div><div>Introduction:</div><div>Pediatric acute lymphoblastic leukemia (ALL) is the most common
pediatric malignancy, affecting approximately 30 cases per million
children and young adults <sup>1,2</sup>. Leukemia and lymphoma
arise from clonal proliferations of abnormal hematopoietic cells or
lymphoid tissue leading to abnormal bone marrow function and malignant
infiltration of tissues, ultimately causing multi-organ failure<sup>3</sup>. Outcomes for patients with childhood leukemia and
lymphoma have drastically improved over the past 30 years, with
exceptional 5-year survival rates of &gt;90% in children and
adolescents with newly-diagnosed disease <sup>4</sup>. It has
been reported that children with public health insurance who develop a
malignancy have inferior long term survival compared with children who
have private health insurance, but there has been no analysis of the
causes for this disparity <sup>5</sup>. One possible etiology may
be the time required for diagnosis of this malignancy. Time from symptom
onset to diagnosis can be a critical period for children with
malignancies, with diagnosis typically preceded by days to weeks of
symptoms that may include fever, night sweats, weight loss, fatigue,
bleeding and bruising <sup>1,2</sup>. Prompt diagnosis and
treatment may lead to an overall decrease in morbidity from associated
complications and in mortality <sup>3</sup>. However, there is a
paucity of data evaluating the extrinsic factors that lead to possibly
significant delays in pediatric ALL and acute lymphoblastic lymphoma
(ALLy) diagnosis. This study sought to elucidate if time to diagnosis is
associated with demographic factors or ALL/ALLy outcomes in a racially
diverse patient population.</div><div>Methods:</div><div>Patients aged 0-25 years old with pre-B cell ALL and acute lymphoblastic
lymphoma were identified (n=274) within the Pediatric Hematologic
Malignancy Cohort (PHMC), a cohort of 444 patients diagnosed with ALL
and ALLy within Montefiore Health System (MHS) from 2004-2017. The PHMC
comprises a combined retrospective cohort of 180 pediatric patients
cared for at the Children’s Hospital at Montefiore and 413 adult and
pediatric aged patients from the Hematological Malignancies Cohort at
MMC (HMCMMC) <sup>6</sup>, which includes all lymphoma and
leukemia patients diagnosed within MHS from 2004-2017. Duplicate
patient information was removed based on Medical Record Number (MRN) and
date of birth (DOB) with demographics, diagnosis date, self reported
race and ethnicity, preferred language, vital status, biologic sex, DOB,
and diagnosis and time of hypertension extracted using Montefiore’s
Electronic Data Warehouse (EDW). Information regarding time from symptom
onset was gathered both through retrospective chart review when
available or data extraction within the EDW based on first contact date
within Montefiore Cancer Registry and diagnosis date when retrospective
chart review was unavailable. Presence or absence of high-risk
cytogenetics was determined through retrospective chart review and
evaluation of historical logbooks within the Molecular Cytogenetics
Laboratory at Albert Einstein College of Medicine, with high-risk
cytogenetics being defined as hypodiploid status, <i>IKZF1</i> mutation,
MLL rearrangement, and intrachromosomal amplification of chromosome 21.
Data on cytogenetic mutations were available on 158 patients in the
PHMC.</div><div>Time from symptom onset to diagnosis was compared by insurance type,
preferred language, biologic sex, vital status, socioeconomic
status11SES was based upon the patient’s census block group and
is reported as a summary Z-score relative to the New York State mean
using 6 variables (additional details in following reference: 7. Roux
AVD, Merkin SS, Arnett D, et al. Neighborhood of Residence and
Incidence of Coronary Heart Disease. <i>New England Journal of
Medicine</i> . 2001;345(2):99-106. doi:10.1056/nejm200107123450205)
(SES), presence of high-risk cytogenetics, and race and ethnicity using
Kaplan Meier curves with log rank testing and Wilcoxon testing<sup>7,8</sup>. Pearson’s Chi-square tests and t-tests were used
to evaluate variables normally distributed after visual inspection with
non-parametric testing used for variables not normally distributed.
Exploratory analyses were performed stratifying the above analyses by
race and ethnicity and presence or absence of high-risk cytogenetics, as
well as by preferred language and an age cut off of 10 years to evaluate
possible surveillance differences by age. Further exploratory analysis
was performed using multivariable logistic regression to identify risk
factors placing patients at risk for prolonged time to diagnosis longer
than 14 days. SES, sex, race/ethnicity, preferred language, vital
status, insurance type, age at diagnosis in years, and high-risk
cytogenetics were compared using univariate analysis. A priori modeling
with race/ethnicity and all variables with p&lt;0.2 in univariate
modeling were included with stepwise backward elimination for final
model building with final model significant only for age at diagnosis
and race/ethnicity. We used Cox Proportional hazard modeling with
similar model building to evaluate above risk factors for development of
hypertension during treatment for ALL and ALLy, with final model
significant only for high-risk cytogenetics. All analyses were conducted
using Stata (Version 17).</div><div>Results:</div><div>Among our ALL/ALLy patients, age at diagnosis (years), biologic sex, and
high-risk cytogenetics did not differ by race and ethnicity (Table 1).
47% of all patients reported Medicaid insurance, while 36% reported
Self-Pay and 17.5% reported having Private insurance. Of those with
Private or Self-pay insurance, 67% reported Self-Pay insurance.
Non-Hispanic Whites had higher socioeconomic status compared to
Hispanics and Non-Hispanic Blacks, while a higher percentage of
Hispanics (75%) had Medicaid insurance compared to 59% of Non-Hispanic
Blacks and 48% of Non-Hispanic Whites (Table 1). 85% of Hispanics were
alive in this cohort, with fewer Non-Hispanic Blacks reported as alive
at end of follow up time (69%; p=0.03) (Table 1).</div><div>Median time to diagnosis in days for all 274 patients was 11.5 (IQR 7.8,
14.3). Median time to diagnosis of ALL and ALLy in days was similar
between Hispanic, Non-Hispanic Black, and Non-Hispanic White
racial/ethnic groups (10.5 vs 14 vs 8; p=0.7), but between male and
female patients, there was a suggestion of a difference (14 vs 10;
p=0.08). Those with Medicaid insurance were diagnosed in less time than
those with private or self-pay insurance (median of 10 vs 16 days;
p=0.05) (Table 2, Figure 1a). Spanish speakers experienced the most time
from symptom onset to diagnosis date compared to English speakers and
those speaking other languages (median of 14 vs 11 vs 7 days; p=0.05)
(Table 2, Figure 1b). Time to diagnosis in days was similar both in
males and females and in each racial/ethnic group (Figure 1c, 1d). Time
to diagnosis in days was similar by vital status and presence of
high-risk cytogenetics. Exploratory analyses observed similar time to
diagnosis trends among racial/ethnic groups and those with or without
presence of high-risk cytogenetics (Supplemental Tables S1, S2). Among
Hispanic patients, there was a suggestion that those with Spanish
language preference experienced a median 14 days to diagnosis compared
to 7 days for Non-Spanish speakers (p=0.08), while median time to
diagnosis of pediatric ALL and ALLy was similar between insurance groups
(p=0.57) (Supplemental Table S3). Among Non-Hispanic patients, there was
a suggestion that those with Private or Self-Pay insurance experienced a
median time to diagnosis of 16 days compared to 9 days for those with
Medicaid insurance for diagnosis of ALL/ALLy (p=0.08), with time to
diagnosis by preferred language similar between groups
(p&gt;0.99) (Supplemental Table S3). Of note, preferred
language was predominantly English among our Non-Hispanic patients with
very few expressing Spanish language preference. Similar results were
demonstrated when insurance was evaluated by Private vs. Self- Pay vs.
Medicaid insurance. Among Hispanic patients, males experienced a median
18 days compared to 7 days for female patients (p=0.01), however, time
to diagnosis was similar between males and females in Non-Hispanics
(Supplemental Table S3). Supplemental analyses comparing Non-Hispanic
English/Other speakers to Hispanic English/Other and Hispanic Spanish
speakers revealed similar findings, with Hispanic Spanish speakers more
likely to have prolonged diagnosis time if male. Those Hispanic
English/Other speaking patients were as likely to have prolonged
diagnosis times as English speakers. Exploratory analysis evaluating
effect of age on time to diagnosis demonstrated similar findings as
above, with those Hispanic male Spanish speakers more prone to prolonged
diagnosis time regardless of age cut off of 10 years. Time experienced
for diagnosis of ALL/ALLy was similar for those reported as alive or
dead (Table 2). Survival outcomes for ALL/ALLy were similar between
racial/ethnic groups (Table 2).</div><div>We found that presence of high-risk cytogenetics was associated with a
reduced risk of development of hypertension, when adjusting for
race/ethnicity and age at diagnosis (HR 0.36; 95% CI 0.14, 0.92). while
time to diagnosis was not associated with development of hypertension.
Further analysis evaluating variables associated with prolonged times to
diagnosis greater than 14 days in multivariable logistic regression
analysis found age at diagnosis as the only variable affecting odds of
experiencing delays in diagnosis in modeling adjusting for age at
diagnosis in years and race/ethnicity.</div><div>Discussion:</div><div>The results of this study demonstrate that time to diagnosis for
pediatric ALL and ALLy differs by both preferred language and insurance
type. Those with Medicaid are diagnosed with ALL or ALLy in a median 10
days, while those with private or self-pay insurance experienced a
median of 16 days to diagnose the same disease. The majority of
non-Medicaid reporting patients had self-pay insurance status,
indicating that a large proportion of patients in our cohort were likely
uninsured. Among Non-Hispanic patients, there was a suggestion of an
observed shift in diagnosis times by insurance status, which was not
apparent in the Hispanic patients. Further studies may elucidate whether
insurance status may play more of a role in the time Non-Hispanics
experience for diagnosis of ALL and ALLy. Common symptoms prior to
diagnosis include fever, weight loss, night sweats, leg pain, difficulty
walking, and easy bleeding or bruising <sup>2,4</sup>. These
symptoms can begin from 1 month to days prior to presenting to care.
When diagnosed at a later stage, pediatric ALL and ALLy can be
associated with a more aggressive disease course, placing patients at
greater risk for long term complications including chronic kidney
disease, hypertension, and neurologic complications from tumor lysis
syndrome and uncontrolled disease <sup>2</sup>. These delays may
be due to a variety of reasons, including avoidance of emergency rooms,
difficulty obtaining a referral to a specialty care provider, or poor
anticipatory guidance and education on warning symptoms at home<sup>9</sup>. Current evidence suggests differences exist between
patient utilization of Emergency Department (ED) care<sup>10</sup>. Studies have found that uninsured children who
were treated in a pediatric outpatient practice were 93% less likely to
utilize ED care. Uninsured children were also 4 times more likely to
utilize ED care for sick visits than those who were insured.<sup>10</sup> The clinical and social aspects of those in our
cohort with self-pay insurance may differ, with individuals likely
having no insurance. Those without insurance may have increased
difficulty presenting for care, both in outpatient and ED settings,
suggesting that utilization of acute care settings does differ by
insurance status, with insurance status as a driver of differential
times to diagnosis of pediatric ALL and ALLy, particularly in
Non-Hispanics in our cohort.</div><div>We observed differences in time to diagnosis by preferred language, with
those speaking Spanish taking a median 14 days for their diagnosis of
pediatric ALL or ALLy. Previous studies have suggested that those who
speak languages other than English may utilize ED care less than English
speaking patients. Differences in ED use in non-English speaking
patients are thought to be due to dissatisfaction with the medical
system, misunderstanding of diagnoses, and differences in health
literacy <sup>9</sup>. In our study, Spanish speaking patients
were more likely to take longer to get diagnosed with ALL or ALLy,
particularly if male. This difference was observed to be more pronounced
in Hispanics, suggesting that Spanish speaking Hispanics may be more
prone to delays in diagnosis due to communication and possible cultural
barriers than those Hispanic patients who speak English. This may be due
to similar factors as seen in previous studies, such as misunderstanding
of the medical system and lack of health literacy, but the role of sex
in differential times to diagnosis requires further study<sup>9</sup>. Improving the language barrier and understanding
cultural norms in pediatric medicine may be beneficial to health
practitioners in helping patients understand their health and alter
their utilization of healthcare, thereby allowing them to have better
outcomes.</div><div>This study has demonstrated that differences exist in the length of time
for the diagnosis of ALL and ALLy based on preferred language and
insurance status. These findings suggest that disparities exist in the
care of those who do not speak English as well as those with
non-Medicaid insurance, with different ethnicities possibly
demonstrating different factors associated with prolonged ALL and ALLy
diagnosis time. With many non-Medicaid patients in our cohort reporting
self-pay insurance, health literacy and cultural/social barriers are
likely playing a role in prolonged diagnosis times for ALL and ALLy.
Improved access to health care may affect one’s time to diagnosis of ALL
and ALLy, thereby reducing the risk of severe complications from
untreated ALL. Our study did not demonstrate increased risk of
hypertension with prolonged diagnosis times but further evaluation of
severe complications could not be performed. Additional analyses in
larger diverse cohorts should be completed to better understand the role
of delays in diagnosis in severe complications from untreated ALL and
ALLy. While the sample size was limited, a total cohort of 274 patients
does represent a large pediatric cohort within an ethnically diverse
population base. A particular strength of this study includes this
diverse population within MHS, a safety net hospital system that serves
a large historically marginalized minority population within the Bronx,
NY and provides care for all individuals, regardless of insurance
status, representing a medical home in which patients can be assured of
continued care regardless of financial or social concerns. Limitations
of this study include that preferred language was extracted from EDW
which may contain inaccuracies. Previous evidence utilizing EMR based
data extraction methods has demonstrated accurate results, however,
reaffirming the utility of data extraction methods in retrospective
analyses <sup>11,12</sup>. The use of preferred language does
allow us to evaluate this Hispanic subset of patients specifically to
determine if there are differences in outcomes in diagnosis of ALL and
ALLy based on the ability to speak limited English. Further research is
needed to confirm results based on exploratory analyses evaluated in
this study in larger populations.</div><div>This study demonstrated that those who are not English speaking and
those who have Non-Medicaid insurance may be prone to longer diagnosis
times of pediatric ALL and ALLy, which may place them at risk for a
variety of conditions throughout therapy, including tumor lysis
syndrome, stroke, cardiovascular compromise, and kidney damage<sup>2,3</sup>. Larger studies should be performed to evaluate
whether time to diagnosis of ALL and ALLy impacts development of these
risk factors. This report suggests that different ethnicities may be
prone to delays in time to diagnosis of pediatric ALL based on different
social and cultural factors, reflecting the need for further research
into the role of social determinants of health on time to diagnosis of
ALL.</div><div>Conflict of Interest: We know of no conflicts of interest associated
with this publication</div><div>Acknowledgements: The research described was supported by NIH/National
Center for Advancing Translational Science (NCATS) Einstein-Montefiore
CTSA Grant Number UL1TR001073 as well as the Cancer Center Support Grant
Number 2P30CA013330 and the Children’s Hospital at Montefiore Fellow
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doi:10.1007/s10552-018-1057-5</div><div>TABLE 1. Demographics by Race and Ethnicity in Pediatric Hematologic
Malignancies Cohort (PHMC) within Montefiore Health System (MHS)</div>