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\begin{document}

\title{Severe Refractory Hemorrhagic Cystitis after Hematopoietic Cell
Transplantation Responds to Recombinant Human Keratinocyte Growth Factor
(KGF) - A Case Report and Review of the Literature}



\author[1]{Michelle Schoettler L}%
\author[1]{Catherine Hughes}%
\author[1]{Anora Harris}%
\author[1]{Benjamin Watkins}%
\author[1]{Muna Qayed}%
\author[1]{Suhag Parikh}%
\author[1]{Edwin Horwitz}%
\author[1]{Elizabeth Stenger}%
\author[1]{Kirsten Williams}%
\affil[1]{Children's Healthcare of Atlanta Inc Aflac Cancer and Blood Disorders Center}%


\vspace{-1em}



  
  \date{May 24, 2024}


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Severe Refractory Hemorrhagic Cystitis after Hematopoietic Cell
Transplantation Responds to Recombinant Human Keratinocyte Growth Factor
(KGF) - A Case Report and Review of the Literature

Catherine Hughes\textsuperscript{1}*, Anora Harris\textsuperscript{1}*,
Benjamin Watkins\textsuperscript{1}, Muna Qayed\textsuperscript{1},
Suhag Parikh\textsuperscript{1}, Edwin Horwitz\textsuperscript{1},
Elizabeth Stenger\textsuperscript{1}, Kirsten M
Williams\textsuperscript{1}, Michelle L Schoettler\textsuperscript{1}

\emph{*co-first authors}

\textsuperscript{1}Aflac Cancer and Blood Disorders Center, Children's
Healthcare of Atlanta, Emory University

Corresponding Author:

Michelle Schoettler, MD

Children's Healthcare of Atlanta, Emory University

Ph 404-727-5381 \textbar{} Michelle.Schoetter@emory.edu

Journal: Pediatric Blood and Cancer

Article Type: Letter to the Editor

Manuscript Word Count: 788 (maximum 850) \emph{no abstract}

References: 13

Figures: 1

Tables: 1

Supplementary Tables: 1

COI: MS- advisor/consultancy to Omeros and Alexion

Authorship: KH and AH wrote the manuscript, the remaining authors edited
the manuscript and cared for the patient.

\textbf{To the Editor:}

Refractory hemorrhagic cystitis (HC) after allogeneic hematopoietic
cellular therapy (HCT) is associated with significant morbidity and
non-relapse related mortality, whether it develops within a few days of
the preparative regimen or after engraftment in the setting of urotropic
viruses.\textsuperscript{1,2} Severe HC includes gross blood and clots
(grade 3) and thrombi that require manual clot evacuation (grade
4)\textbf{(Supplemental Table 1} ). Currently, there are no standard
treatments for refractory grade 3 or 4 HC after HCT.

We present a 16 -year-old male who underwent a matched sibling donor
bone marrow transplant for myelodysplastic syndrome with a busulfan and
cyclophosphamide myeloablative conditioning regimen. Grade 3 HC
developed within 24 hours after cyclophosphamide completed (day 0). His
infectious work-up at diagnosis, including BK and adenovirus virus were
negative at that time. His HC was attributed to cyclophosphamide though
he received MESNA and appropriate hydration. He developed autoimmune
hemolytic anemia on day +37 which was treated with methylprednisolone,
rituximab, sirolimus, and daratumumab. He remained transfusion dependent
due to his ongoing AIHA and HC, which persisted despite hyperhydration
and supportive care with phenazopyridine and oxybutin. On day +54 post
HCT, he was noted to have BK viruria and, despite intravenous cidofivir,
had progressive grade 4 HC on day + 62 requiring cystoscopy and manual
clot evacuation. His HC was treated with ciprofloxacin, estrogen, and
intravesicular cidofovir. Despite these interventions, he had persistent
grossly bloody urine with large clots and required an additional 2
manual clot evaluations and cystoscopies. Red blood cell transfusions
were required daily to every other day despite resolution of hemolysis
markers with anemia and were attributed to HC. On his
6\textsuperscript{th} re-admission for supportive care for refractory HC
(total days inpatient 91), novel therapies were considered due to lack
of response to published therapies and diffuse hemorrhage in the bladder
precluding cautery in the setting of physiologic steroids and ongoing
cidofovir. In an attempt to avoid bladder toxicity from experimental
agents, recombinant human keratinocyte growth factor (rH-KGF) was
initiated at 60 mcg/kg three times a week based on limited clinical
data.\textsuperscript{3,4,5} Within 48 hours of the first rH-KGF dose,
his hematuria improved to grade 2 and he became transfusion independent.
Over the next 2 weeks, his hematuria improved to grade 1, with full
resolution of HC 17 days after his first dose of rH-KGF. Of note,
systemic steroids for his AIHA had been weaned to physiological dosing
36 days prior to initiation of rH-KGF and BK viruria was downtrending
significantly at the time of starting rH-KGF. While it is possible that
HC resolution was unrelated to the drug, given the temporal relationship
and lack of prior response to other agents, this is unlikely. From
transplant day until completion of rH-KGF he received a total of 85 PRBC
units; after resolution of HC, he remained RBC transfusion independent.
He is 1 year post HCT and completely recovered without urinary symptoms
though he has persistent mild chronic kidney disease \textbf{(Figure
1).}

HC is a well-known complication following hematopoietic stem cell
transplant (HCT).

The incidence of HC post-HCT is increasing, in part due to increasing
application of haploidentical HCT, and there is no consensus to guide
the best therapy severe refractory grade 3 or 4 HC, though data support
attempting bladder irrigation, intravesicular therapy, estrogen,
hyperbaric oxygen therapy.\textsuperscript{6,7} Additional therapies
such as cidofovir or T cells targeting BK have been employed for viral
associated HC.\textsuperscript{8} Intravesical irrigation with agents
such as formalin, alum, and prostaglandin may be considered, but have
limited data to support use and may be associated with short and long
term effects including altered mental status, refractory bladder spasms,
renal failure, and urinary incontinence.\textsuperscript{9,10}

rH-KGF is FDA approved to reduce severe oral mucositis in patients with
hematologic malignancies HCT patients, but has been used off label as a
rescue agent in severe, refractory HC cases. rH-KGF binds to KGF
receptors, resulting in proliferation, differentiation, and migration of
epithelial cells. KGF receptors have been reported to be present on
areas such as the tongue, esophagus, stomach, liver, kidney, and
bladder.\textsuperscript{11} Studies in rats have demonstrated that
administration of recombinant human KGF results in proliferating cell
nuclear antigen expression along the basal layer of urothelium and
protection against cyclophosphamide-induced ulcerative
HC.\textsuperscript{3,12} Given that HC is characterized by damage,
inflammation, and bleeding to the bladder mucosa, rH-KGF has been used
for its urothelium related restorative properties in 2 other published
severe, refractory HC cases (\textbf{Table 1} )\textsuperscript{4,5}

In summary, we report rapid response of severe, refractory HC to rH-KGF
in a child post HCT and add to the limited data on this subject. Given a
favorable side effect profile, particularly compared to more invasive
approaches like intra-vesicular administration of scarring agents,
consideration of this drug is merited in severe, refractory HC.

\textbf{Table 1. Summary of Evidence of Use of Keratinocyte Growth
Factor for Treatment of Hemorrhagic Cystitis Post Stem Cell Transplant}\selectlanguage{english}
\begin{longtable}[]{@{}lllll@{}}
\toprule
\textbf{Reference} & \textbf{Subject(s)} & \textbf{Failed HC Treatments}
& \textbf{Keratinocyte Growth Factor (KGF) Course} &
\textbf{Outcome}\tabularnewline
\midrule
\endhead
Ulich TR et al.\textsuperscript{3} & 15 male Sprague Dawley rats given
cyclophosphamide & not applicable & 5 mg/kg given once 24 hours prior to
cyclophosphamide. & 12 of 15 (80\%) of the rats did not have ulcerations
of the bladder epithelium.\tabularnewline
Czibere A et al.\textsuperscript{4} & 24-year-old male with refractory
T-acute lymphoblastic leukemia given conditioning with fludarabine,
high-dose cytarabine, amsacrine, and total body irradiation prior to
stem cell transplant & permanent bladder irrigation, cidofovir,
intravenous immune-globulins, oral estrogens & 60 mcg/kg given three
days a week for 15 total doses. Intravesical Uropol S was also given at
this time. & Bleeding stopped after 12 doses. Hematuria reappeared a few
days later, but resolved after 1 additional week of
treatment.\tabularnewline
Bhaskaran S et al.\textsuperscript{5} & 12-year-old female with relapse
acute myeloid leukemia given conditioning with busulfan,
cyclophosphamide, and rabbit antithymocyte globulin prior to stem cell
transplant & bladder irrigation, intra-vesicular cidofovir,
intra-vesicular prostaglandin E2, cidofovir, hyperbaric oxygen & 60
mcg/kg given three days a week for 4 weeks. Hyperbaric oxygen was
continued. & Complete resolution of gross hematuria 2 weeks after
initiation of palifermin.\tabularnewline
\bottomrule
\end{longtable}

Figure 1: Treatment Course of Patient with Severe, Refractory
Hemorrhagic Cystitis and Responses\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/image1/image1}

\end{center}
\end{figure}

Treatment of an adolescent with severe, refractory hemorrhagic cystitis
(HC). Despite aggressive treatment of HC with supportive care, cidofovir
when BK virus detected, ciprofloxacin, estrogen and 2 manual clot
evacuations with intravesicular cidofovir, he remained symptomatic with
significant pain, bleeding, and red cell transfusion dependent. After
treatment with human keratinocyte growth factor, his refractory HC
improved, and ultimately resolved.

\textbf{References:}

\begin{enumerate}
\tightlist
\item
  Harkensee C, Vasdev N, Gennery A, et al. Prevention and management of
  BK-virus associated haemorrhagic cystitis in children following
  haematopoietic stem cell transplantation -- a systematic review and
  evidence-based guidance for clinical management. \emph{Br J Haematol}
  . 2008;142(5):717-31.
\item
  De Padua Silva L, Patah P, Saliba R, et al. Hemorrhagic cystitis after
  allogeneic hematopoietic stem cell transplants is the complex result
  of BK virus infection, preparative regimen intensity and donor
  type.\emph{Haematologica.} 2010. July; 95(7):1183-1190.
\item
  Ulich TR, Whitcomb L, Tang W, et al. Keratinocyte growth factor
  ameliorates cyclophosphamide-induced ulcerative hemorrhagic
  cystitis.\emph{Cancer Res} . 1997;57(3):472-5.
\item
  Czibere A, Bruns I, Graef T, et al. Treatment of severe hemorrhagic
  cystitis after allogeneic stem cell transplantation with palifermin, a
  recombinant human keratinocyte growth factor. \emph{Biol Blood Marrow
  Transplant.} 2007;13(7):872-4.
\item
  Bhaskaran S, Abu-Arja RF, Abusin G, et al. Recombinant human
  keratinocyte growth factor: successful treatment of severe, refractory
  hemorrhagic cystitis after allogeneic hematopoietic cell
  transplantation. \emph{Bone Marrow Transplant.} 2014;49(12):1550-1.
\item
  Yuan H, Chen G, Xu J, et al. Incidence of late-onset hemorrhagic
  cystitis and its effect on PFS in acute leukemia patients after
  haplo-PBSCT: the 5-year single-center data. \emph{Front Oncol} .
  2022;12:913802.
\item
  Thompson A, Adamson A, and Payne H. Guidelines for the diagnosis,
  prevention and management of chemical- and radiation induced
  cystitis.\emph{J Clin Urol} . 2013;7:25-35.
\item
  Dave H, Luo M, Blaney JW, et al. Toward a rapid production of
  multivirus-specific T cells targeting BKV, Adenovirus, CMV, and EBV
  from umbilical cord blood. \emph{Mol Ther Methods Clin Dev} .
  2017;5:13-21.
\item
  Abt D, Bywater M, Engeler DS, et al. Therapeutic options for
  intractable hematuria in advanced bladder cancer. \emph{Int J Urol} .
  2013;20(7):651-60.
\item
  Westerman ME, Boorjian SA, Linder BJ. Safety and efficacy of
  intravesical alum for intractable hemorrhage cystitis: a contemporary
  evaluation. \emph{Int Braz J Urol} . 2016;42(6):1144-1149.
\item
  Palifermin {[}package insert{]}. Stockholm, Sweden: Swedish Orphan
  Biovitrum; 2023.
\item
  Yi ES, Shabaik AS, Lacey DL, et al. Keratinocyte growth factor causes
  proliferation of urothelium in vivo. \emph{J Urol} .
  1995;154(4):1566-70.
\item
  Droller MJ, Saral R, Santos G. Prevention of cyclophosphamide-induced
  hemorrhagic cystitis. \emph{Urology} . 1982;20(3):256-8.
\end{enumerate}

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