Challenging Case:Hemorrhagic Cystitis

Amy Wiglesworth Bryk, PharmD, BCOP, BCPS

Clinical Pharmacist Lead

Humana

Disclosures

• I have no relevant conflicts of interest to disclose.

• This presentation contains discussion of published and/or investigational uses that are not indicated by the FDA. Please refer to the official prescribing information for each product for discussion of approved indication, contraindications and warnings.

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Learning Objectives

• Identify risk factors associated with hemorrhagic cystitis (HC) after hematopoietic stem cell transplant (HCT)

• Summarize therapeutic options for treating HC after HCT

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Patient Introduction

• Mrs. K: 61 year old female

• Oncologic history

—Severe aplastic anemia: Received eltrombopag + immunosuppressive therapy

—High-grade MDS: Received decitabine x 4 cycles

—Nonmyeloablative haploidentical peripheral blood HCT 4/2015

• Conditioning: fludarabine, cyclophosphamide, TBI

• Transferred for blood in the urine in 9/2015

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Hemorrhagic Cystitis

Grade 1 Grade 2 Grade 3 Grade 4 Grade 5

Microscopic hematuria with

symptoms

Macroscopic hematuria

Macroscopichematuria with small

clots

Gross hematuria with clots causing

urinary obstruction and renal failure

Massive hemorrhage resulting in death

DelaCruz J, et al. Curr Infect Dis Rep. 2014;16:417.

De Padua Silva L, et al. Haematologica. 2010;95:1183-90.5

• Occurs in up to 70% of HCT recipients

• Associated with significant morbidity and prolonged hospitalization

delaCruz J, et al. Curr Infect Dis Rep. 2014;16:417.6

Signs & Symptoms

Dysuria

Urinary frequency

Urinary urgency

Suprapubic pain

Hematuria

Possible Complications

Severe bladder pain

Significant blood loss

Prolonged hospital stay

Renal failure

Bladder rupture

Diagnosis

Symptoms of cystitisGrade ≥ 2 hematuriaBK viruria > 7 log10

copies/mL

Risk Factors for HC

De Padua Silva L, et al. Haematologica. 2010;95:1183-90.

Giraud G, et al. Haematologica. 2006;91:401-4.

Lunde LE, et al. Bone Marrow Transplant. 2015;50:1432-37.7

Rimondo A, at al. Bone Marrow Transplant. 2017;52:135-7.

delaCruz J, et al. Curr Infect Dis Rep. 2014;16:417.

Cesaro S, et al. J Antimicrob Chemothera. 2018;73:12-21.

Donors Conditioning regimen

Immunesuppression

Infections Risk of Bleeding

Allogeneic

Unrelated donors

Cord blood

Haploidentical

Myeloablative conditioning

Antithymocyte globulin

Tacrolimus

Acute GVHD

BKV+ in urine or serum

CMV

HHV-6

Thrombocytopenia

Factors associated with increased immunosuppression or immune dysfunction are associated with higher rates of HC

Causes of HC in HCT Population

delaCruz J, et al. Curr Infect Dis Rep. 2014;16:417.

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Early HC 24-72 hours after HCT

Late HC > 2 weeks after HCT

Often drug-induced:Cyclophosphamide

Viral infections:BK virus (BKV)

AdenovirusCytomegalovirus (CMV)

Fungal or bacterial infections

GVHD

Malignancy

BK Virus (BKV)

• Non-encapsulated DNA polyomavirus

• >80% seropositivity in adults

• Transmission in childhood

• Reactivation of latent virus in the kidneys or urothelium may occur during immunosuppression

• HC is a well-recognized complication of BKV infection in HCT recipients

Ambalathingal GR, et al. Clin Microbiol Rev. 2017;32:503-28.

Phillipe M, et al. Biol Blood Marrow Transplant. 2016;22:723-30.9

BKV-Induced Disease

• Asymptomatic BKV viruria – 50-80% of allogeneic HCT patients

• BKV-hemorrhagic cystitis (BKV-HC) – reported incidence 7-54% of alloHCTpatients

—Ranges from asymptomatic hematuria and self-limited illness to a more severe disease process requiring clinical interventions

—As early as 10 days post-HCT, but typically 2-8 weeks post-HCT

—Associated with increased transplantation costs and poorer OS

• Ureteral stenosis

• Interstitial nephritis/nephropathy

delaCruz J, et al. Curr Infect Dis Rep. 2014;16:417.

Cesaro S, et al. J Antimicrob Chemothera. 2018;73:12-21. 10

Knowledge Check

What is the most common cause of late-onset HC after HCT?

A. Radiation

B. GVHD

C. BKV

D. Cyclophosphamide

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delaCruz J, et al. Curr Infect Dis Rep. 2014;16:417.12

Conventional methods:• Mesna• Hydration

Questionable benefit: • Continuous bladder

irrigation• Fluoroquinolones

Prevention

• Antivirals?• Intravenous immune

globulin (IVIG)?• Intravesical agents to

locally control bleeding?• Cystectomy• Virus specific T-cells

RefractoryTreatment

Initial Treatment

• Aggressive IV hydration• Forced diuresis• Pain control• Continuous bladder

irrigation

• Inpatient management for severe symptoms for macrohematuria with clots

• Cystoscopy for clot removal• Platelet or blood transfusions to control/prevent bleeding

Back to Mrs. K

HC treatment:

• Bladder cauterization (prior to transfer)

• IVIG

• Intravesicular aminocaproic acid

• Intravesicular carboprost

• Conjugated estrogen

• Phenazopyridine and oxybutynin for bladder spasms

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BKV-Directed Antiviral Therapies

Phillipe M, et al. Biol Blood Marrow Transplant. 2016;22:723-30.

Toptas T, et al. Oncol Lett. 2014;8:1775-7.

Chen X, et al. Acta Haematol. 2013;130:52-6.

Cesaro S, et al. J Antimicrob Chemothera. 2018;73:12-21. 14

Medication Dosing Response Rate Toxicities

Cidofovir

12 retrospectiveand 2 prospective studies; n=210

Standard dose: 3- 5 mg/kg/dose with probenecid

Clinical response: 74% Nephrotoxicity • May be mitigated by low-dose or intravesical

administration• Avoid other nephrotoxic medicationsNausea/vomitingMyelosuppressionBladder irritation and pain (intravesical route)

Low dose: ≤ 1.5 mg/kg/dose withoutprobenecid

Clinical response: 83%

Intravesical: 5 mg/kg/dose withoutprobenecid

Clinical response: 43%

Leflunomide

2 retrospective studies; n=19

Example: 100 mg PO daily x 3 days, then 20 mg daily

Complete response: 64%Partial response: 26%

GI toxicityImmunosuppression, myelosuppressionHepatotoxicity

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Treatments for Refractory HC

Treatment Mechanism Response Rate Toxicities

IntravesicalAlum

Stimulates vasoconstriction, decreases capillary permeability and causes sclerosis of exposed capillary endothelium

60% in review of 40 patients with refractory HC

Bladder spasms, transient delirium, UTI, asymptomatic increase in blood aluminum.

Silver Nitrate Cauterizing agent. Produces nitric acid when combined with water.

No response in review of 9 patients with refractory HC

None noted

Formalin Capillary occlusion and protein fixation at the level of the urothelium

75% response in review of 8 patients with refractory HC

Bladder contracture, reduced bladder capacity, hydroureternephrosis, acute kidney injury, and urinary tract fistulae

Hyperbaric Oxygen

Promotes tissue healing and angiogenesis through steep oxygen gradient

Various case reports and series, n=20; Complete clinical response: 86%

Barotraumatic otitis, visual disturbances, and paresthesia.

Westerman ME, et al. Int Braz J Urol 2016;42:1144-9.

Montgomery BD, et al. Turk J Urol. 2016;42:197-201.

Ziegelmann MJ, et al. Can Urol Assoc J. 2017;11:E79-82. 15

Cardinal J, et al. Current Urol Rep. 2018:19:38.

Yenerel MN, et al. Turk J Hematol. 2009;26:176-80.

Cesaro S, et al. J Antimicrob Chemothera. 2018;73:12-21.

Additional Treatments for Refractory HC

Lakhami A, et al. Bone Marrow Transplant. 1999;24:1259-60.

Singh I, et al. Urology. 1992;40:227-9.

Cesaro S, et al. J Antimicrob Chemothera. 2018;73:12-21. 16

• Intravesical aminocaproic acid

• Prostaglandins

• IVIG

• Estrogens

• Fibrin glue application

• Cystectomy

T-Cell Adoptive Immunotherapy

Transfer of ex vivoisolated or generated virus-specific T cells from autologous or allogeneic sources

Davies SI, Cytotherapy. 2017;19:1302-16.17

ACP: antigen presenting cellCAR-T: chimeric antigen receptor T-cellPBMCs: peripheral blood mononuclear cells TCR: T-cell receptorVST: virus-specific T cells

PBMCs collected from patient or healthy donor

T cell expansion

VSTs infused into patient

Patient

Donor

Natural stimulation

and isolation of VSTs

Engineered VSTs

Production of TCR or CAR-T

Constructs

Cytotoxic activity

analyzed

Antigen presentation to T cells

APCs incubated with viral peptide mix

Transduction of T cells

Surface expression of virus-specific

construct

Virus Specific T-cells (VSTs)

Stem-cell donor-derived

• Board implementation limited by—Cost and complexity of individualized

product manufacturing

—Time needed to manufacturing (not immediately available for urgent cases)

—Donor must be seropositive for virus of interest

Tzannou I, et al. J Clin Oncol. 2017;35:3547-57.18

Third-party

• “Off the shelf”

• Manufactured from third-party donors to recognize one or more viruses

• Partially HLA-matched

Off-the-Shelf VSTs after AlloHCT

• Bank of VSTs that recognized EBV, AdV, CMV, BKV, and HHV-6

• 38 patients received VSTs

• BKV specific results —16 patients, 14 with BKV HC

—13/14 BKV HC patients with CR of gross hematuria by week 6 post infusion

—One patient able to proceed to 2nd HCT due to resolved hematuria

• AdV specific results —7 patients: 4 CRs, 1 PR, 2 nonresponses

—One patient with AdV-associated pneumonitis and HC with a PR

Tzannou I, et al. J Clin Oncol. 2017;35:3547-57.19

AdV: adenovirusCMV: cytomegalovirus

EBV: Epstein-barr virusHHV-6: human herpesvirus-6

Knowledge Check

Which of the following treatments for refractory HC or BKV-HC is least likely to provide clinical benefit:

A. Intravesical silver nitrate

B. Cidofovir

C. Virus-Specific T-cells

D. Leflunomide

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Summary

• HC occurs in up to 70% of patients after alloHCT, most commonly caused by BKV.

• While supportive measures are often sufficient, patients with refractory HC may require BKV-directed antiviral therapy or one of a number of different intravesical or systemic treatments. Data supporting any of these treatment modalities is not robust.

• While more data is needed, VSTs provide a promising cellular therapy for BKV-HC.

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References

Cesaro S, Dalianis T, Rinaldo CH, et al. ECIL guidelines for the prevention, diagnosis and treatment of BK polyomavirus-associated haemorrhagic cystitis in haematopoietic stem cell transplant recipients. J Antimicrob Chemother.2018;73:12-21.

delaCruz J, Pursell K. BK Virus and Its role in Hematopoietic Stem Cell Transplantation: Evolution of a Pathogen. Curr Infect Dis Rep. 2014;16:417.

Tzannou I, Papadopoulou A, Naik S, et al. Off-the-Shelf Virus-Specific T Cells to Treat BK Virus, Human Herpesvirus 6, Cytomegalovirus, Epstein-Barr Virus, and Adenovirus Infections After Allogeneic Hematopoietic Stem-Cell Transplantation. J Clin Oncol. 2017;35:3547-57.

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