challenging case: hemorrhagic cystitis · lunde le, et al. bone marrow transplant. 2015;50:1432-37....
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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.
2
Learning Objectives
• Identify risk factors associated with hemorrhagic cystitis (HC) after hematopoietic stem cell transplant (HCT)
• Summarize therapeutic options for treating HC after HCT
3
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
.
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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