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.1,2 Severe HC includes gross blood and clots
(grade 3) and thrombi that require manual clot evacuation (grade 4)(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
6th 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.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 (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.6,7 Additional therapies
such as cidofovir or T cells targeting BK have been employed for viral
associated HC.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.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.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.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 (Table 1 )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.