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\begin{document}

\title{Subcutaneous Administration of Cytarabine for Pediatric Patients with
Langerhans Cell Histiocytosis Decreases Burden of Patient Travel and
Infusion Center Utilization}



\author[1]{Jennifer R. Blase}%
\author[1]{Aarti Kamat}%
\author[2]{David Frame}%
\author[1]{Rama Jasty}%
\author[1]{Kelly Walkovich}%
\affil[1]{University of Michigan}%
\affil[2]{University of Michigan College of Pharmacy}%


\vspace{-1em}



  
  \date{June 13, 2024}


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\selectlanguage{english}
\begin{abstract}
Both vinblastine and low dose cytarabine therapy for Langerhans cell
histiocytosis (LCH) have historically been delivered intravenously. Due
to a vinblastine shortage and the SARS-CoV2 pandemic, frontline
subcutaneous cytarabine was used to treat six pediatric patients with
LCH with greater than 93\% of the cytarabine doses administered at home
by family. On average, 164 infusion chair hours (65.7 infusions) and
5,607 miles of driving were saved per patient, highlighting that
subcutaneous cytarabine is a feasible treatment option for pediatric
patients with LCH resulting in notably decreased patient travel burden
and infusion center utilization.%
\end{abstract}%



\sloppy


\textbf{TITLE PAGE}

\textbf{Title:} Subcutaneous Administration of Cytarabine for Pediatric
Patients with Langerhans Cell Histiocytosis Decreases Burden of Patient
Travel and Infusion Center Utilization

\textbf{Authors:}

Jennifer R. Blase, MD, PhD\textsuperscript{1}

Aarti Kamat, MD\textsuperscript{1}

David Frame, PharmD\textsuperscript{2}

Rama Jasty-Rao, MBBS\textsuperscript{1}

Kelly Walkovich, MD\textsuperscript{1}

\textbf{Affiliations:}

Division of Pediatric Hematology/Oncology, Department of Pediatrics,
University of Michigan, Ann Arbor, MI, USA

College of Pharmacy, University of Michigan, Ann Arbor, MI, USA

\textbf{Corresponding Author:}

Jennifer R. Blase, MD, PhD

Research Fellow, Pediatric Hematology \& Oncology

University of Michigan

1500 East Medical Center Drive

Ann Arbor, MI 48109

Phone: 734-936-9814

Fax: 734-232-8740

Email: jblase@med.umich.edu

\textbf{Word Count:}

Abstract = 93 words

Main Text = 1189 words

\textbf{Number of Tables/Figures} = 2 (1 tables + 1 figure)

\textbf{Short Running Title} (max 50 characters): Subcutaneous
cytarabine in pediatric LCH

\textbf{Keywords (3-6):} Langerhans cell histiocytosis, pediatric
hematology/oncology, cancer pharmacology, chemotherapy, quality of life

\textbf{Abbreviations Key} (for main text, not table)\selectlanguage{english}
\begin{longtable}[]{@{}ll@{}}
\toprule
\textbf{Abbreviation} & \textbf{Full Phrase}\tabularnewline
\midrule
\endhead
CR & Complete response\tabularnewline
IRB & Institutional review board\tabularnewline
IV & Intravenous\tabularnewline
LCH & Langerhans cell histiocytosis\tabularnewline
PR & Partial response\tabularnewline
\bottomrule
\end{longtable}

\textbf{Abstract:}

Both vinblastine and low dose cytarabine therapy for Langerhans cell
histiocytosis (LCH) have historically been delivered intravenously. Due
to a vinblastine shortage and the SARS-CoV2 pandemic, frontline
subcutaneous cytarabine was used to treat six pediatric patients with
LCH with greater than 93\% of the cytarabine doses administered at home
by family. On average, 164 infusion chair hours (65.7 infusions) and
5,607 miles of driving were saved per patient, highlighting that
subcutaneous cytarabine is a feasible treatment option for pediatric
patients with LCH resulting in notably decreased patient travel burden
and infusion center utilization.

\textbf{Introduction} :

Langerhans cell histiocytosis (LCH) is an inflammatory myeloid neoplasia
commonly involving the skin, bones, and/or pituitary\textsuperscript{1}.
Historical standard of care treatment with intravenous (IV) vinblastine
and oral prednisone has led to high 5-year overall survival rates (99\%
for low-risk, 87\% for high-risk disease), but there are still high
rates of relapsed or refractory disease (37\% for low-risk, 39\% for
high-risk disease)\textsuperscript{2}. Due to its effectiveness in
treating relapsed/refractory LCH\textsuperscript{3}, single agent, low
dose IV cytarabine is currently being compared directly to vinblastine
and prednisone as frontline LCH treatment in a randomized control
clinical trial\textsuperscript{4}.

The 2019 prolonged vinblastine shortage in the United
States\textsuperscript{5,6} forced consideration of cytarabine as
upfront therapy for LCH. This was immediately followed by the SARS-CoV2
pandemic, which resulted in pressures to minimize in-hospital exposures
and reduce infusion room utilization. With these constraints, we
utilized frontline cytarabine delivered primarily subcutaneously in six
pediatric LCH patients from 2019 to 2022, based on sharing decision
making with patients and their families. Herein, we report the clinical
responses of the cohort, highlighting both the feasibility of in home
administration of subcutaneous cytarabine and decreased patient travel
burden and infusion center utilization.

\textbf{Methods} :

Review of pediatric LCH cases from 2019-2022 was authorized by
University of Michigan IRB with informed consent waived, in accordance
with local research regulations. Six patients who received frontline
cytarabine monotherapy at 100 mg/m\textsuperscript{2}/dose for 5 days,
every 21-28 days, to complete 14 cycles were identified. Cytarabine was
administered via subcutaneous injection at home, and intravenously or
subcutaneously when administered in inpatient hospital or infusion
center. Oral trametinib was added to treatment regimen for patients 4
and 6, due to lack of complete response, at a dose of 0.02 mg/kg/dose
(rounded to nearest 0.25 mg, max 2 mg) given once daily.

Disease evaluation imaging was performed at baseline and after 2 cycles,
4 cycles (if not yet in CR), and end of
therapy.\emph{BRAF\textsuperscript{V600E}} mutation analysis was
evaluated by local immunohistochemistry stain on tissue biopsy and by
external CLIA-certified quantitative PCR assay on peripheral blood.
Complete response (CR) was based on RECIST imaging criteria, lack of
metabolic activity on PET/CT, and eradication
of\emph{BRAF\textsuperscript{V600E}} cells in peripheral blood (if
present at diagnosis). Partial response (PR) was defined by RECIST
imaging criteria, residual metabolic disease on PET/CT, or residual,
detectable peripheral blood \emph{BRAF\textsuperscript{V600E}} .

\textbf{Results} :

\emph{Demographics} . Six pediatric LCH patients were treated with
upfront cytarabine monotherapy (Table 1). Patients ranged from 18 months
to 15 years at time of diagnosis (average 8 years). Patients 3, 4, and 6
had multisystem LCH, patients 1 and 2 had multifocal osseous LCH, and
patient 5 had localized disease, but high CNS risk given pituitary
involvement. Half had the classic
\emph{BRAF\textsuperscript{V600E}}mutation present either on tissue
biopsy or peripheral blood.

\emph{Chemotherapy dose administration location} . Following one
instructional session performed in clinic by a registered nurse, 93.81\%
of cytarabine doses were administered subcutaneously at home by
patients' parents, while the remainder were administered in the infusion
center or inpatient hospital (Figure 1). Home administration saved
patients an average of 65.7 infusion days, translating to 164 infusion
chair hours per patient. Additionally, patients saved an average of
5,607 miles (range 3,024 -- 7,560 miles) of driving throughout the
course of their 12-month therapy, versus if they had to travel to the
infusion center each of the five days per treatment cycle.

\emph{Adverse events} . All six patients tolerated cytarabine treatment
well, with minimal adverse events. Blood counts were monitored weekly,
and while 5 of 6 patients experienced grade II anemia, none required red
blood cell or platelet transfusions. There was an average of 0.5
hospital infusion visits per patient for indications other than
chemotherapy (range 0-2), all for central access or de-access. Patients
had an average of 1.67 emergency department visits (range 0-4), for
fever or other infectious symptoms (all grade I), and an average of 0.67
hospital admissions (range 0-2), either for initial chemotherapy (i.e.
for increased monitoring for patients with central diabetes insipidus)
or for neutropenic fever (only one patient experienced grade III febrile
neutropenia).

\emph{Outcomes.} All six patients completed 14 cycles of cytarabine,
with four achieving a CR and two achieving a PR (Table 1). CR's occurred
early following the second cycle in patient 1 and fourth cycle in three
patients. In the two patients with a PR, one achieved a CR after
addition of oral trametinib, and one had improvement on PET CT, MRI, and
clinical skin exam, but continued to have positive peripheral
blood\emph{BRAF\textsuperscript{V600E}} testing at end of cytarabine
treatment and therefore was initiated on oral trametinib therapy.

\textbf{Discussion} :

While cancer drug shortages, e.g. the vinblastine shortage, directly
impact patient treatment selection\textsuperscript{6}, the SARS-CoV2
pandemic influenced therapeutic decisions with a unique aspect of
minimizing in-person interactions when safe and feasible. In fact, a
survey of oncology providers during the SARS-CoV2 pandemic found that
47\% changed treatment selection to specifically reduce in-person
visits\textsuperscript{7}. Given that LCH-III treatment involves up to
26 infusion center visits for intravenous
vinblastine\textsuperscript{2}, and the current phase 3 randomized
control trial comparing vinblastine to cytarabine involves 70 infusion
center visits for intravenous cytarabine\textsuperscript{4}, we
similarly sought strategies to reduce in-person visits for LCH care with
a transition to subcutaneous cytarabine.

Subcutaneous cytarabine is regularly used at equivalent dosing to
intravenous cytarabine in pediatric patients with hematologic
malignancies, at a similar low dose as used in this case
series\textsuperscript{8,9}. Its use in LCH was recently described in
three pediatric patients as well\textsuperscript{10}. Interestingly,
subcutaneous cytarabine may have outcome advantages over short infusion
intravenous administration with a higher area under the curve,
potentially resulting in higher intracellular
concentrations\textsuperscript{11}, without the requirement for central
venous access.

This case series demonstrates that subcutaneous cytarabine
administration was palatable to LCH patients and their families,
requiring a single nurse education session to learn the proper technique
for subcutaneous injections. Importantly, subcutaneous therapy was also
safe, with only one grade III adverse event occurring (uncomplicated
febrile neutropenia). Furthermore, patients had only 0.5 infusion visits
for indications other than chemotherapy and only 1.67 emergency
department visits. No blood transfusions were required in this cohort.

Over 93\% of all cytarabine doses were administered at home, offering
patients more flexibility and less time missing work or school.
Subcutaneous cytarabine saved patients and their families an average of
5,607 miles of driving to and from medical centers throughout the
yearlong course of therapy, with patients living 27-63 miles from the
hospital, likely having positive downstream effects on decreasing
financial pressures related to travel. Utilizing subcutaneous cytarabine
saved an average of 65.7 infusion visits per patient, totaling 164 hours
of infusion chair time. While this was especially important during the
SARS-CoV2 pandemic, it remains valuable as pediatric infusion centers
work to manage escalating patient volumes.

The clinical responses observed suggest that subcutaneously administered
cytarabine is safe and feasible in pediatric LCH patients. This may have
additional benefits, especially improving access to care for patients
geographically distanced from pediatric LCH specialists/infusion
centers, considering opting out of central lines and offering
opportunities for improved quality of life while receiving LCH therapy.
However, prospective trials are needed to determine the optimal
frontline therapy for pediatric LCH, with at least two currently
ongoing\textsuperscript{4,12}.

\textbf{Conflicts of Interest:}

Author K. Walkovich discloses the following potential conflicts of
interest: she is the local principal investigator for the Mavorixafor
trial (sponsored by X4 Pharmaceuticals); she is a member of the steering
committee for Sobi; and she is on the advisory board for Sobi, Pharming,
AstraZeneca, Horizon, and X4 Pharmaceuticals. None of these are relevant
to this study however. The remaining authors have no relevant conflicts
of interest to disclose.

\textbf{References} :

1. Allen CE, Merad M, McClain KL. Langerhans-Cell Histiocytosis. \emph{N
Engl J Med} . Aug 30 2018;379(9):856-868. doi:10.1056/NEJMra1607548

2. Gadner H, Minkov M, Grois N, et al. Therapy prolongation improves
outcome in multisystem Langerhans cell histiocytosis. \emph{Blood} . Jun
20 2013;121(25):5006-14. doi:10.1182/blood-2012-09-455774

3. Donadieu J, Bernard F, van Noesel M, et al. Cladribine and cytarabine
in refractory multisystem Langerhans cell histiocytosis: results of an
international phase 2 study. \emph{Blood} . Sep 17 2015;126(12):1415-23.
doi:10.1182/blood-2015-03-635151

4. Eckstein O. Randomization of cytarabine monotherapy versus
standard-of-care vinblastine/prednisone for frontline treatment of
Langerhans Cell Histiocytosis (TXCH LCH0115). ClinicalTrials.gov
identifier: NCT02670707. Updated June 12, 2023. Accessed July 7, 2023.
https://www.clinicaltrials.gov/study/NCT02670707

5. Rabin RC. Faced with a drug shortfall, doctors scramble to treat
children with cancer. \emph{New York Times} . October 14, 2019. Accessed
July 7, 2023.
https://www.nytimes.com/2019/10/14/health/cancer-drug-shortage.html

6. McBride A, Hudson-DiSalle S, Pilz J, et al. National Survey on the
Effect of Oncology Drug Shortages in Clinical Practice: A Hematology
Oncology Pharmacy Association Survey. \emph{JCO Oncol Pract} . Aug
2022;18(8):e1289-e1296. doi:10.1200/OP.21.00883

7. Arem H, Moses J, Nekhlyudov L, et al. Oncology provider experiences
during the COVID-19 pandemic. \emph{PLoS One} . 2022;17(7):e0270651.
doi:10.1371/journal.pone.0270651

8. Maloney KW, Devidas M, Wang C, et al. Outcome in Children With
Standard-Risk B-Cell Acute Lymphoblastic Leukemia: Results of Children's
Oncology Group Trial AALL0331. \emph{J Clin Oncol} . Feb 20
2020;38(6):602-612. doi:10.1200/JCO.19.01086

9. Angiolillo AL, Schore RJ, Kairalla JA, et al. Excellent Outcomes With
Reduced Frequency of Vincristine and Dexamethasone Pulses in
Standard-Risk B-Lymphoblastic Leukemia: Results From Children's Oncology
Group AALL0932. \emph{J Clin Oncol} . May 1 2021;39(13):1437-1447.
doi:10.1200/JCO.20.00494

10. Eckstein OS, Bernhardt MB, Hood CG, Karri V, Kralik SF, McClain KL.
Treatment of Langerhans cell histiocytosis with subcutaneous
cytarabine.\emph{Pediatr Hematol Oncol} . Jan 10 2023:1-9.
doi:10.1080/08880018.2022.2137609

11. Liliemark JO, Paul CY, Gahrton CG, Peterson CO. Pharmacokinetics of
1-beta-D-arabinofuranosylcytosine 5'-triphosphate in leukemic cells
after intravenous and subcutaneous administration of
1-beta-D-arabinofuranosylcytosine. \emph{Cancer Res} . May
1985;45(5):2373-5.

12. North American Consortium for Histiocytosis. LCH-IV, international
collaborative treatment protocol for children and adolescents with
Langerhans Cell Histiocytosis. ClinicalTrials.gov identifier:
NCT02205762. Updated March 23, 2023. Accessed July 7, 2023.
https://www.clinicaltrials.gov/study/NCT02205762

\textbf{Legends:}

\textbf{Table 1.} Patient Case Summary

\textbf{Figure 1.} Delivery location of chemotherapy administration.
Each patient received a total of 70 doses of cytarabine (14 cycles, each
5 days), for a total of 420 doses for the 6 patients described. 394 of
the 420 doses (93.81\%) were administered subcutaneously at home by
patients' parents, while the remaining 26 doses (6.19\%) were
administered either in hospital infusion center or inpatient hospital.\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/Blase-LCH-Figure1/Blase-LCH-Figure1}

\end{center}
\end{figure}

\textbf{Hosted file}

\verb`Blase_LCH_Table1.docx`  available at \url{https://authorea.com/users/640015/articles/655138-subcutaneous-administration-of-cytarabine-for-pediatric-patients-with-langerhans-cell-histiocytosis-decreases-burden-of-patient-travel-and-infusion-center-utilization}

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