Hemorrhagic

Cystitis

S. S. BadriResident of Clinical Pharmacy

معرفی بیمار

ساله 4/5 کودک .ف نرگس بیمار و وزن کمبود سبب به مراجؼه :سالگی سه در

سر دور سایس بودن کوچک

← Fanconi anemia

استخوان مغس پیونذ مرکس به مراجؼه :90/7/21 شریؼتی بیمارستان

ساله 13 برادر از HSC پیونذ دریافت جهت(Full-match)

DH : Folic

acid, Oxymetholone, Danazol

Fanconi anemia

• DefinitionA genetic disease with an incidence of

1 per 350,000 births.

Congenital aplastic anemia :

pancytopenia

macrocytic anemia

congenital malformations

progressive bone marrow failure

increased incidence of malignancies.

• DiagnosisBefore the age of 16

• TreatmentSupportive modalities

Androgens

hematopoietic growth factors

A large number of responders ultimately become refractory to such treatment or developintolerable side effects

Allogeneic HCT is the only treatment option that can restore normal hematopoiesis.

FA is the result of a genetic defect in a cluster of proteins responsible for DNA repair.

As a result, the majority of FA patients develop cancer, most often acute myelogenous leukemia, and 90% develop BM failure (the inability to produce blood cells) by age 40.

About 60-75% of FA patients have congenital defects, commonly :

short stature,

abnormalities of the skin, arms, head, eyes, kidneys, and ears,

developmental disabilities.

Fanconi anemia

Indications Severe bone marrow failure

Myelodysplastic syndrome (MDS)

Acute myelogenous leukemia

HLA-identical related donor :

As soon as severe marrow failure develops.

Before the patient becomes dependent on transfusions.

Without an HLA-identical related donor :

HCT generally is not recommended until failure of other treatmentmodalities, including androgens and transfusions.

HSC Transplantation

34

35

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Tem

per

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D -

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D -

1

D 0

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1

D +

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D +

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D +

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D +

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D +

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D +

13

D +

15

D +

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D +

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D +

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D +

25

D +

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35

D +

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D +

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D +

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Allo-PB

Days

Complications

Mu

cosi

tis

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t G

VH

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V

Hem

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↑

Gut

GV

HD

II

Cat

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CM

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Gut

GV

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IV

Sei

zure

Cyst

ost

om

y

TP

N

4

روزD -8

D -4Amp Mesna 100 mg , stat Amp Mesna 130 mg + Bicarbonate 10 cc , inf. over 3 hrs.

Amp Endoxan 190 mg + D/W 5% 250 cc 9 - 12 AM

Amp Mesna 150 mg + Bicarbonate 20 cc + D/S 100 cc 9 AM-3 PM

Amp Mesna 350 mg + Bicarbonate 30 cc + D/S 400 cc 3 PM-9 AM

Busulfan

Amp Phenytoin

Syrup Phenytoin

4

روز

Chemotherapy

Chemotherapy

D -2

D 0

D +1

D +2

D +3

D +6

Amp Cyclosporine 19 mg (1.5 mg/kg)

Drugs → Hold (Ex. Cyclosporine)

HSC Transplantation (Allo-PB)

Amp MTX 6 mg (10 mg/m2)

Amp Leucovorin 5 mg, QID

Amp MTX 3.5 mg (6 mg/m2)

Amp MTX 3.5 mg (6 mg/m2)

D +4

D +7

D +10

D +17

Hematuria

Gross Hematuria

BK virus ? Amp Ciprofloxacine 130 mg, IV, BD

.احتباس ادراری نذارد. بیمار هماچوری دارد.نیاز به اقذام خاصی از نظر هماچوری نذارد

↑ Hematuria↑ Dysuria

لخته از ادراردفغ

DysuriaSupportive care

D +27

D +32

D +35

D +36

سونذاش← مشاوره اورولوشی اورشانسی تا خروج لخته ها و N/Sسی سی 200دو نوبت شست و شوی مثانه با

clear شذن ترشحات

Continuous vesical irrigationN/Sسی سی 100ساػت شست و شو با 2هر

.ادرار بیمار کامالً به صورت دفغ لخته استHgbافت

↑ HematuriaSonography → Hydronephrosis

Clot شذن سونذ .سونذخروج ←شست و شو باز نشذ با

شذیذهمچنان هماچوری Alumمشاوره جهت تعیین دوز

D +39

D +40

D +45

سونذاش مجذدادامه شست و شوAlum 1% → کاهش دفغ لخته

Amp Novoseven 800 mcg, IV, statInf. over 20 min

ادرارادامه دفغ خون از ادامه شست و شو

.P.Cنوبت دریافت دو

Novosevenشروع

(N/Sسی سی 100ساػت با 2هر )ادامه شست و شو ادامه دفغ لختهModerate HydronephrosisConfusion

D +46

D +47

D +49

D +51

ادامه هماچوریHgbافت

Cystostomy

clearترشحات از راه سونذ . است functionسونذ بیمار بذون

(هماچوری)دفغ از مجرای ادراری به صورت لخته خروج سونذ← functionبذون همچنان ← اورولوشیمشاوره

Gross Hematuriaدرد شذیذ در مجرای ادراری

←سونوگرافی

Plan : Cystectomy → مشاوره جراحی

In transplantation settings, HC is a complication associated with HSCT, but occurs

rarely in solid organ recipients.

Hemorrhagic inflammation in urinary tract mucosa

Symptoms :

asymptomatic microscopic hematuria to frank hematuria with clot formation and

urinary tract obstruction.

may be a life-threatening complication.

despite recovery from HC, transplanted patients who experienced HC had lower

overall and event-free survival compared with patients who did not experienced HC.

Early & Late onset HC :

Time elapsed after the conditioning regimen.

Early → starts within 48–72 h after the conditioning regimen

Late occurs beyond this time.

Early → toxicity of high-dose chemo- and/or radiotherapy

Late → multiple factors including viral infections

Hemorrhagic Cystitis

• Cyclophosphamide

Acrolein was identified as an urotoxic metabolite of cyclophosphamide and hyperhydrationand preventive treatment with mesna were introduced into prevention ofcyclophosphamide-induced HC.

• Radiation : days or years after the treatment.

• Viral infection as a contributing factor to post-engraftment HC after HSCT.

Qualitative and Quantitative association between BKV and HC

Pathophysiology

Only incidence of cyclophosphamide-associated HC has been reduced with preventive

treatment.

Once HC is established, the treatment principles are similar regardless of the etiology and

depend on the intensity of HC.

Accepted Management

Prevention of urinary tract obstruction,

Transfusion support,

Analgesic,

Spasmolytic therapy

• Qualitative and Quantitative association between BKV and HC

BK-virus

Three-phase model of post-engraftment HC :

1- The conditioning regimen causes the damage to uroepithelium resulting in asuitable environment for replication of BKV.

2- The immunosuppressive treatment allows for virus reactivation in the secondphase,

followed by recognition and destruction of infected uroepithelial cells by donorlymphocytes leading to

3- Tissue damage in the third phase.

PCN = percutaneous nephrostomy

• Only incidence of cyclophosphamide-associated HC has been reduced withpreventive treatment.

• Once HC is established, the treatmentdepends on its severity.

• Microscopic hematuria with little or noclinical symptoms usually resolvesspontaneously.

• Several approaches have been reported forthe treatment of severe HC with inconclusiveresults, and thus, no standard and evidence-based approach has been widely adopted.

Prevention & treatment

Mesna and Hyperhydration

Acrolein was identified as an urotoxic metabolite of cyclophosphamide about three decadesago.

Forced diuresis with or without bladder irrigation has been used to prevent HC by diluting theacrolein concentrations in the urine.

Uroprotective mesna (sodium 2-mercaptoethane sulfonate) has been developed and is widelyaccepted as a prophylactic agent against oxazaphosphorines-induced HC.

Mesna was compared with hyperhydration or bladder irrigation in 3 studies :

Shepherd et al. studied the incidence of hematuria in 100 adult patients randomized either to mesna with hydration 1.5L/m2/day or hyperhydration with 3 L/m2/day from the start of cylophoshamide infusion until 48 h after the end ofcyclophosphamide infusion.

The authors found that mesna was as effective as hyperhydration.

Hows et al. reported 61 transplanted patients that were randomized to treatment with either mesna or hyperhydration.The patients in the mesna arm received 3 L dextrose saline over 24 h, while the patients in the hydration group weretreated with 6 L over 24 h and urine alkalinization.

The incidence of hematuria in the mesna treated group was lower compared with hyperhydrationalone.

In another prospective study, 200 patients were randomized either to treatment with mesna or bladder irrigation. Allpatients received intravenous hydration with normal saline.

Despite that the overall incidence of HC was lower in the mesna treated group, no difference in theoccurrence of grade III and IV HC was observed.

Systemic prevention

1

2

3

• Mesna is widely accepted as a prophylactic treatment for cyclophosphamide-induced HC in HSCT.

• However, HC still occurs in 10-40% of mesna-treated patients.

Ciprofloxacin

• Fluoroquinolones : in vitro activity against BKV.

• Possible prophylactic effect

Systemic prevention

Hyperhydration, urine alkalinization, and mesnaremain so far the corner stone in prevention ofcyclophosphamide-induced HC during HSCT.

Considering the controversial outcomes of studies and obviousdiscomfort associated with continuous bladder irrigation, theroutine use of this preventive treatment in children remainsdoubtful.

Local prevention

Continuous bladder irrigation

Clotting factors

rFVIIa rFVIIa was originally developed for the treatment of bleeding in hemophiliacs who hadinhibitors against factor concentrates. However, promising results of the treatment withrFVIIa have also been reported in other types of bleeding including hemato-oncologicaland stem cell transplantation-related hemorrhage.

Activated FVII acts through the tissue-factor-dependent and -independent pathways, bothresulting in the formation of a ‘‘thrombin burst,’’ essential for the formation of a stablefibrin clot.

In one multicenter, randomized, double-blind, placebo-controlled study, 100 patients ≥12 yr old withmoderate or severe bleeding were randomized to rFVIIa in doses 40, 80 or 160 μg/kg · 7 (administeredwithin 36-h period) or placebo in addition to standard management procedures.

Despite that the overall response (complete or partial) was 57% and rFVIIa in a dose of 80μg/kg resulted in significant improvement of bleeding compared with placebo, the authorswere unable to demonstrate any clinical benefit of the treatment with rFVIIa in terms ofcontrol of hematuria.

Severe adverse events were equally distributed across the treatment groups.

Systemic Treatment

Local treatment – intravesical

Alum

Indwelling of a Foley catheter and bladder irrigation with isotonic salt solution.

Alum (aluminum ammonium sulfate or aluminum potassium sulfate)

Decreased capillary permeability,

Contraction of the intercellular space,

Vasoconstriction,

Hardening of the capillary endothelium,

Reduction of edema and inflammation caused by the astringent action of proteinprecipitation at the cell surface and superficial interstitial spaces.

Bladder irrigation with alum is quite a common strategy in severe HC.

No large clinical trials in transplanted patients have been reported.

Risk for alum intoxication (confusion, encephalopathy, cardiomyopathy, and coma) has tobe considered, especially in children.

Alum

Alum

Alum

Supportive Treatment

Hyperhydration,

Forced diuresis,

Transurethral catheter for intermittent or continuous bladder irrigation,

Clot evacuation,

Transfusion support,

Pain and Spasm control

Important parts of management of HC regardless of etiology.

Thank You

hemorrhagic cystitis

Sepideh Elyasi

Resident of clinical pharmacy

Biol Blood Marrow Transplant 17:1176-1181, 2011

Introduction: BK virus-associated hemorrhagic cystitis (BKHC) occurs in 12% to

40% HSCT recipients.

Present in the urinary tract of 80% of adults.

In allogeneic HSCT patients, the chemotherapy and irradiation from

the conditioning regimen cause damage to the urothelium cooperating

with immunosupresive state to trigger viral replication and shedding,

alloimmune attack to the urothelium, and finally bleeding.

Clinical manifestations of BKHC can be minor, with asymptomatic

hematuria, but can be severe, causing massive blood loss, pain,

urinary obstruction, renal failure, and even death

Occurs typically beyond 30 days after

transplantation (and usually after 72hrs)

Most cases of BKHC are mild and self-limited,

but there are no treatments proven to be effective

in decreasing the morbidity or the duration of

severe episodes.

Ciprofloxacin carries inhibitory activity against

the prokaryotic DNA gyrase subunit A, can

prevent BK virus replication in vitro

Methods: All adult patients undergoing allogeneic HSCT at the Medical

University of South Carolina (MUSC) received phrophylaxis:

Board were reviewed retrospectively to collect patients data who

undergoing allogeneic HSCT at MUSC between January 2006 and

August 2010

Prior to march 2009

from the day of transplantation until neutrophil engraftment

(typically, the third consecutive day of neutrophils .500/mm3)

consisting of ciprofloxacin 500 mg orally every 12 hours

After march 2009 Institute prophylaxis with ciprofloxacin from day 0 until day 60

after transplantation

BKHC was defined as the presence of hematuria, concomitant urinary

excretion of BK virus as detected by PCR

Episodes of BKHC were graded as grade 1, microscopic hematuria;

grade 2, macroscopic hematuria; grade 3, macroscopic hematuria with

small blood clots grade 4, massive macroscopic hematuria requiring

instrumentation of the urinary tract or causing urinary retention

Occurrence of grades 3 and 4 BKHC, called severe BKHC, as an

endpoint for the study

The main endpoint of the study was to compare the cumulative

incidence of severe BKHC between the group of patients receiving

prophylaxis with ciprofloxacin (PC) and the group not receiving

prophylaxis (NP).

Results:

Melphalan >140 mg/m2 and/

or total-body irridiation (TBI)

.500 cGy (single fraction) or

800 cGY (multiple fractions)

and/or busulfan .8 mg/kg

4 patients: allergy

36 patients: discontinued

ciprofloxacin because of fever

and neutropenia

8 patients: discontinued at the

time of neutrophil engraftment

There were 11 cases of severe BKHC in the NP group and

1 case in the PC group, occurring after a median of 68.5

(range: 30-118) days after transplantation.

Severe BKHC occurred in 9 of 38 (23.7%) patients with

and in 3 of 54 (6.1%) patients without clinically

significant (grades B-D) aGVHD (P =.024).

11 of 43 (25.6%) patients receiving a myeloablative

conditioning regimen developed severe BKHC compared

to only 1 of 49 (2%) patients receiving a reduced intensity

conditioning (P=.001).

risk

20.9%

2.6%

20.9%

2.6%

There is concern that the prolonged use of antibiotic

prophylaxis after transplantation may lead to increased risk for

infection by antibiotic-resistant pathogens and Clostridium

difficile diarrhea.

There were 28 episodes of bacteremia in NP versus 7 episodes

of bacteremia in PC patients (P = .003) however, bacteremias

developing in the setting of ciprofloxacin prophylaxis were

more likely to be caused by a fluoroquinolone-resistant

pathogen which demand caution.

There was no significant difference in occurrence of episodes

of Clostridium difficile diarrhea among the groups with 3

episodes in NP and 5 episodes in PC (P = .48).

Discussion:

The current analysis suggests that this intervention is both safe

and effective, with a near 90% reduction in the risk to develop

severe BKHC and none of the patients in the PC cohort

discontinuing therapy prior to day 60 after transplantation.

The impact of prophylaxis remained significant even in

multivariate analysis, along with factors demonstrated in prior

series to be implicated in BKHC, namely, GVHD and

myeloablative conditioning.

there is preliminary evidence that levofloxacin also can be

effective in preventing BK virus–associated complications after

kidney transplantation

Limitations:

The main limitation of this report is its

retrospective nature, only partially overcome by

the multivariate analysis.

Even though unaccounted differences in

supportive care between cohorts may have

affected the outcome, this is unlikely to be the

case, because all the transplants in both cohorts

occurred during a relatively short period of time

(56 months) with no other interim substantial

change in supportive care practices.

Introduction:

Hyperbaric oxygen (HBO) has already been used

extensively and successfully for the treatment of

hemorrhagic cystitis (HC). But the cost is high and the

treatment is still not available in most hospitals in China

who lack the hardware.

Intravesical instillation of hyaluronic acid (HA) has

shown some benefit in the treatment of HC . Because of

its ease of use and safety, it is valuable to evaluate the

efficacy of intravesical HA in the treatment of radiation-

induced HC

36 patients who underwent

radiotherapy for their pelvic malignancies

from November 2004 to

December 2008 who subsequently

suffered from HC

the HA group ( n = 16), 40 mg of HA was slowly instilled into the

bladder of the patients through a Foley catheter. Then clamped for

a minimum of 20 min. All patients received intravesicalinstillation weekly in the first

month and then monthly in the

following 2 months.

The HBO group ( n = 20),patients received

100% oxygen in a hyperbaric chamber at a pressure of 2.5 atm absolute, 60 min, once a

day, 7 days a week, for at least 1 month and were

followed up over 18 months.

randomly

Method:

therapeutic efficacy was evaluated every 6 months up to

18 months.

Initial response was defined as the day when amelioration

of symptoms appeared

complete response (CR) was defined as the day on which

all symptoms including macroscopic haematuria, dysuria

etc. disappeared.

Disappearance of clots but with persistence of

macroscopic haematuria was defined as partial response

(PR).

Results:

only one case in the HA group

took a second course of HA

instillation 15 months after the first

HA treatment due to HC recurrence.

No obvious side effect of

intravesical HA was recorded

except urinary tract infection due to

repeated urethral catheterization

At 6, 12 and 18 months after

treatment, the improvement rate

showed no statistical difference

between the two groups.

Discussion:

Since there are no well controlled trials available comparing the

existing treatment options, firm guidelines cannot be made.

Under the condition of HBO, alveolar, arterial and tissue oxygen

levels are driven to supraphysiological levels, thereby stimulating

angiogenesis, fibroblast proliferation and collagen formation.

Initially concerns were raised regarding the risk of tumor growth

because of HBO-mediated angiogenesis, immunosuppression and

free radical toxicity. Following a review of all the available

literature in 2003, Fieldmeier and Hampson concluded that HBO

had no more than a neutral effect on tumor growth.

HA exhibits a variety of properties that may contribute to its

prophylactic mechanism , which include inhibition of immune

complexes, adherence to poly-morphonuclear cells, inhibition

of leucocyte migration, regulation of fibroblast and endothelial

cell proliferation, enhancement of connective tissue healing etc.

A damaged glycosaminoglycan layer may lead to direct

exposure of epithelial cells to components of urine; for this

reason the possibility of bacterial adherence and infection

increases. This damage is proposed to be a causative factor in

the development of HC especially due to HSCT.

In this study, intravesical HA can provide sustained

amelioration of hematuria of HC just as well as HBO.

Despite its slightly higher incidence of urinary tract

infection, intravesical instillation of HA is cheaper and

much more convenient than HBO treatment. Intravesical

HA can be an alternative therapy in the management of

radiation-induced HC, although part of its efficacy may

decrease after 12 months.

The main limitation of this study was the small number of

patients and the relatively short follow-up time.

Thank you for attention