Hemorrhagic cystitis (HC) is a therapy-related complication characterized by the presence of continuous macroscopic hematuria occurring in absence of gynecologic and urologic disease or bacterial and fungal infections of the urinary tract.1-5 With symptoms ranging from hematuria to renal failure, HC significantly affects the quality of life, prolongs hospitalization, and in some cases can become an intractable and life-threatening disease. Discrepancies in defining the diagnostic criteria are partially responsible for the variability of HC incidence, which ranges from 10 to more than 60 percent in the setting of allogeneic hematopoietic stem cell transplant (HSCT). Two different clinical forms of HC are known: 1) early cystitis, occurring in the first week after transplant, usually attributed to the side effects of acrolein, a cyclophosphamide metabolite, and 2) late cystitis, occurring more than 10 days after transplant usually lasting between a week and several months. According to the severity of hematuria, HC can be divided into four grades: Grade 1 = microscopic hematuria; Grade 2 = macroscopic hematuria; Grade 3 = hematuria with clots, requiring transfusion support; and Grade 4 = macroscopic hematuria with clots and impaired renal function.2,3 Type of HSCT, the pretransplant conditioning regimen, and the presence of acute graft-versus-host disease (GVHD) have been identified as significant factors related to the onset of HC.1-6 Reactivation of polyoma BK virus (BKV), GVHD higher than Grade 2, transplant from unrelated volunteer, or cord blood donor and recipient age of more than 28 years have been significantly correlated with higher incidence of clinically overt Grade 2 or higher HC.1-5 HC refractory to conventional therapies (hyperhydration, bladder irrigation, antiviral drugs, and transfusion support) is very difficult to treat and no standard care has been established. We report the results of a pilot study on the treatment of refractory HC by using fibrin glue (FG) endoscopic application on bladder mucosa in five high-risk patients undergoing allogeneic HSCT.
BACKGROUND: Patients undergoing hematopoietic stem cell transplant (HSCT) are particularly exposed to the risk of developing hemorrhagic cystitis (HC), which is characterized by symptoms ranging from macroscopic hematuria to renal failure. Although HC significantly affects the quality of life and in a few cases becomes intractable leading to patient death, its therapeutic management has not been established. Fibrin glue (FG), a hemostatic agent derived from human plasma, has been largely employed in different surgical settings including urologic procedures.
STUDY DESIGN AND METHODS: In this pilot study we used FG to treat refractory HC. During cystoscopy, bladder distension was maintained at a constant pressure of 12 mmHg by a carbon dioxide insufflator. An endoscopic applicator allowed spraying FG on the bleeding and raw surfaces of bladder mucosa.
RESULTS: Five of 221 patients undergoing an HSCT developed a very severe, refractory HC and have been treated with endoscopic FG. The treatment was successful in 3 patients; the response was partial in 1 patient and transient in the last one, whose clinical course was severely complicated by acute graft-versus-host disease and multiple organ failure.
CONCLUSIONS: FG therapy is a feasible procedure and this pilot study suggests that it may be an effective treatment for refractory HC. Its application could be considered also in Grade 1 or 2 HC to prevent progression of damaged mucosa. The use of FG for HC should be prospectively investigated in terms of therapeutic efficacy, transfusion support, length of hospitalization, quality of life, and costs.
hematopoietic stem cell transplant.
MATERIALS AND METHODS
This pilot study included patients who met the following selection criteria: Grade 3 or higher HC not responding to hyperhydration, continuous bladder irrigation, antiviral treatments, and transfusion support with platelet (PLT) concentrates.
FG production and application technique
FG was obtained from virus-inactivated fresh-frozen human plasma (Octaplas, Vienna, Austria) and produced using Vivostat system (Vivolution, Birkeroed, Denmark), an automatic method for processing and applying FG starting from both whole blood or fresh-frozen plasma (FFP). The entire process generates approximately 6 mL of sealant from 120 mL of the patient's own blood or FFP in approximately 30 minutes. The Vivostat system is a medical device for the perioperative preparation and application of fibrin sealant in the operating room. The system is made up of three components: an automated processor unit, an automated applicator unit, and a disposable single-patient-use unit, which includes a preparation set and the endoscopic applicator. Details of the biochemical process of the Vivostat system have been reported elsewhere.7 The particular endoscopic system for FG application allows the solution to be spread evenly over the hemorrhagic area; thus, small amounts of sealant can be delivered accurately on the damaged bladder tissue. The sealant polymerizes on contact and sets over several days. Patients underwent conventional cystoscopy to define type and extension of mucosal lesions and to perform clot evacuation (Figs. 1A and 1B). The cystoscopy was performed with a 24F nephroscope (Olympus, Hamburg, Germany) to allow the insertion of the FG endoscopic application system. A laparoscopic carbon dioxide insufflator (LAP 2000, Sofar Medica, Milan, Italy) connected to the nephroscope maintained the bladder distension at a constant pressure of 12 mmHg. The endoscopic FG applicator was inserted through the lumen of the nephroscope and the glue was sprayed on the bleeding and raw surfaces of bladder mucosa (Figs. 1C-1E). Particular care was taken to avoid FG application over the ureteral orifices. The median volume of FG used was 10 mL (range, 6.3-15 mL). At the end of the procedure, a final cystoscopy with low carbon dioxide insufflation pressure checked the FG adhesion and hemostatic efficacy. In the absence of active bleeding areas (Fig. 1F), a Foley catheter without bladder irrigation was positioned. The procedure, well tolerated by the patients, lasted a median time of 45 minutes (range, 35-90 min). The Foley catheter was removed between 2 and 10 days after the procedure on the disappearance of hematuria.
Between January 2006 and June 2007, 221 patients registered at the Rome Transplant Network underwent a hematopoietic stem cell autologous (n = 157) or allogeneic (n = 64) transplant for malignant and nonmalignant diseases. No autologous HSCT recipients developed HC of severe grade, whereas 5 of 64 patients (8%) who had received an allogeneic HSCT met the criteria to enter the study. Of these 5 patients, 3 had been submitted to a haploidentical HSCT, 1 an HLA-matched unrelated transplant, and 1 an HLA-mismatched unrelated cord blood transplant (Table 1).
|Characteristic||UPN 230||UPN 234||UPN 243||UPN 246||UPN 5387|
|Number of previous therapy lines||4||2||10||1||4|
|Disease status at HSCT||PR||CR||PR||CR||Relapse|
|Type of HSCT||CBT||HAPLO||MUD||HAPLO||HAPLO|
|Day to neutrophil engraftment||+17||+21||+12||+23||+22|
|Acute GVHD grade||0||0||III||0||0|
|Day to HC onset||+65||+36||+28||+51||+30|
|Grade of HC||3||3||3||3||3|
|Viruria||CMV, BKV, JCV||BKV||BKV, CMV||BKV||BKV|
|Number of RBC units/week||2||3||3||4||2|
|Number of PLT doses/week||2||5||2||5||2|
Characteristics of individual patients with HC
A 46-year-old female affected by CD30-positive non-Hodgkin's lymphoma, treated with five subsequent lines of therapy for recurrent disease, underwent an unrelated HLA-mismatched cord blood transplant in partial remission of the disease. Full donor engraftment was documented at Day +17. From Day +65, the patient complained of increased urinary frequency with pain and gross hematuria (Grade 3). Median values of hemoglobin (Hb) and PLTs were 8 g per dL and 40 × 109 per L, respectively. Symptoms did not improve after therapy with foscarnet, hydration, continuous bladder irrigation, and transfusion support with 2 units of red blood cells (RBCs) and two doses of PLT concentrates per week. On Day +85 the patient was submitted to cystoscopy with FG application (15 mL). During the first week after the procedure, she experienced nicturia and mild hematuria, but transfusion support was discontinued and Hb levels and PLT counts progressively increased. Despite multiple reactivations of BK and JC viruria, requiring treatment with cidofovir, neither symptoms nor signs of HC have been observed, and with a follow-up of 10 months from transplant the patient is still alive and well.
A 41-year-old female with FLT3-positive acute myeloid leukemia in first complete remission received a haploidentical HSCT from her mother. The patient engrafted with full donor chimerism at Day +21 and no sign of acute GVHD after transplant was observed. From Day +36, she developed symptoms of HC reaching a Grade 3 with gross hematuria and vesical clots. At the echographic examination, the right ureter was partially occluded by the presence of numerous clots with consequent hydronefrosis. The levels of Hb at 7 g per dL and of PLTs at 30 × 109 per L were maintained with transfusion support of 2 to 3 units of RBCs and five doses of PLT concentrates per week, respectively. Hyperhydration, continuous bladder irrigation, and antiviral therapy with cidofovir, administered for BKV-positive viruria, were unsuccessful. The patient underwent the FG application (6.3 mL) for refractory HC at Day +38 after transplant. After the procedure, some episodes of gross hematuria were observed, but they were transient and did not require any PLT transfusion. Symptoms of HC disappeared in 10 days and the echography documented the recovery from the hydronefrosis. BKV viruria remained positive until 3 months after the FG application, but no recurrence of HC was observed. After a follow-up of 11 months, the patient with full donor chimerism is alive and well in complete remission.
After 10 lines of therapy, a 45-year-old woman affected by Sezary syndrome underwent an allogeneic HSCT from an HLA-matched, unrelated marrow donor. Full donor engraftment occurred at Day +12 after transplant. On Day +28, the patient developed urinary frequency and pain that progressed to gross hematuria. The urine was positive for the presence of BKV and cytomegalovirus (CMV), and the patient was treated with cidofovir without improvement of HC symptoms (Grade 3). Hyperhydration, bladder irrigation, and transfusion support were given without response over 21 days. She needed 3 units of RBCs and two doses of PLT concentrates per week to maintain the Hb value at 8 g per dL or greater and PLT counts at 80 × 109 per L or greater to decrease hematuria. The cystoscopy showed several large areas of active bleeding and 10 mL of FG was applied to all raw surfaces. The patient only had a transient benefit from the procedure and her transfusion support remained high concomitantly with the occurrence of a Grade III acute GVHD and multiple CMV reactivations. At 96 days from transplant and 66 days after the onset of HC, the patient died of multiple organ failure.
A 28-year-old male underwent HSCT from a related haploidentical donor for Ph+ lymphoid blastic crisis. The patient engrafted with full donor chimerism at Day +23 after transplant. No sign of GVHD was observed. At Day +51, he developed Grade 3 HC with dysuria, nycturia, gross hematuria, and clots. Polymerase chain reaction became positive for BKV and therapy with cidofovir was administered. All standard therapies for HC were unsuccessful with persisting hematuria and large clots, which required three to four RBC transfusions and five doses of PLT concentrates per week. During cystoscopy, large amounts of clots were removed and FG (8 mL) was diffusely applied on the bleeding areas. The patient had a moderate improvement from the symptoms of HC and vesical catheter was removed only for a transient period. The clinical course was complicated by a persistent CMV disease, thrombocytopenia refractory to PLT transfusions, and pulmonary fungal infection, contributing to the patient's death, which occurred at Day +139 after transplant and at 106 days from the HC.
A 17-year-old girl affected by Hodgkin's lymphoma in progression after four lines of therapy including an autologous transplant, received a haploidentical HSCT from her mother. The neutrophil engraftment occurred at Day +22 and no sign of acute GVHD was observed. At Day +30 from HSCT, the patient developed higher urinary frequency and vesical pain that progressed to frank hematuria. Hyperhydration, bladder irrigation, and transfusion support were given without response. The urine was positive for the presence of BKV at the onset of HC that was classified as Grade 3. The PLT count was 30 × 109 per L and PLT transfusions two times a week were required. To prevent the extension of the bladder's bleeding areas, the patient underwent the FG endoscopic application within a short time (7 days) from the onset of the HC: hematuria discontinued over 24 hours after the application of 10 mL of FG. Until 4 weeks after instillation, no clot passage was observed and symptoms of suprapubic pain or pressure have not been referred. The patient did not require further transfusion support.
In patients receiving HSCT from an allogeneic donor, changes in bladder mucosa after high-dose chemotherapy and urinary injuries from several viral infections can lead to life-threatening hemorrhage either immediately or chronically.1-4 For HC refractory to conventional therapies, several medical approaches such as the use of formalin,8 alum,9 prostaglandin E2,10 hyperbaric oxygen,11 administration of recombinant Factor VII,12 estrogen,13 cidofovir,14 intravesical instillation with sodium hyaluronate,15 and, more recently, infusion of mesenchymal stem cells16 have been employed. Despite the encouraging results reported in some cases, the experiences are limited and related to the expertise of a single transplant center. Most of these therapies are very expensive and sometimes complicated by relevant side effects like bladder fibrosis, urinary incontinence, or renal or nervous toxicity. Invasive and particularly aggressive approaches such as fulguration, vesical artery embolism, nefrotomy, urethral resection, or partial or total cystectomy have been variably proposed as ultimate therapeutic options in extremely debilitated patients with intractable and life-threatening forms of HC.17
FG, a hemostatic agent derived from human plasma coagulation proteins, is largely employed in different surgical settings including urologic procedures with favorable results.18,19 In contrast to synthetic adhesives, fibrin sealants have the advantage of being biocompatible and biodegradable and they are not associated with inflammation, foreign body reactions, tissue necrosis, or extensive fibrosis. To our knowledge, only two cases with refractory HC after HSCT and successfully treated with FG have been reported.20,21
Our experience includes five patients, deeply immunosuppressed after allogeneic HSCT undergoing the FG vesical application for refractory and very severe HC during cystoscopy. The treatment was successful in three patients, whereas a partial response was transiently achieved in one patient. The last patient not responding to FG application is difficult to evaluate because the clinical course was severely complicated by acute GVHD and multiple organ failure.
The visual means through a cystoscope and the rotation of an endoscopic catheter spraying the glue over the damaged areas represent the main advantages for an appropriate application of the fibrin adhesive in the bladder. Spraying the glue together with CO2 insufflation keeps the bladder under constant pressure in order to avoid overflow and overdistension. FG produced by the Vivostat system provides some technical advantages with respect to other conventional devices such as enhanced instant adhesion, strength, and elasticity due to fast polymerization, airflow rates, and spray forces lower and less variable than in conventional systems and more consistent thickness of the fibrin film.7 Furthermore, blockage of the spray system was rare on intermittent use. Owing to the rapid adhesion to human tissue, the risk of FG washing away by blood or urines is reduced by using the Vivostat system. This effect could be important to promote the tissue repair process. The results of this pilot study suggest that the endoscopic application of FG, despite a small risk of infectious disease transmission that cannot be definitively excluded, should be considered a safe and simple therapeutic tool for the management of refractory HC developing in frail and highly immunocompromised patients. Moreover, the procedure could be repeated in case of HC relapse. As an early hemostatic and reparative effect of the FG on the bladder mucosa may prevent the extension of the damaged areas, FG therapy should be applied early from the onset of HC. The use of FG for treating HC should be prospectively investigated on a large patient series to better define, with respect to the current management measures, its impact in terms of therapeutic efficacy, transfusion support, length of hospitalization, quality of life, and costs.
We thank Mrs Marzia Mazzaroni, all the nursing team of the hematology ward, and the staff from the anesthesiology and surgery departments for their excellent work.