Hemorrhagic Cystitis Complicating Bone Marrow Transplantation
LOUIS LETENDRE, M.D., H. CLARK HOAGLAND, M.D., MORIE A. GERTZ, M.D., Division of Hematology and Internal Medicine
Hemorrhagic cystitis is a potentially serious complication of high-dose cyclophosphamide therapy administered before bone marrow transplantation. As standard practice at our institution, patients who are scheduled to receive a bone marrow transplant are treated prophylactically with forced hydration and bladder irrigation. In an attempt to obviate the inconvenience of bladder irrigation, we conducted a feasibility trial of uroprophylaxis with mesna, which neutralizes the hepatic metabolite of cyclophosphamide that causes hemorrhagic cystitis. Of 97 patients who received standard prophylaxis, 4 had symptomatic hemorrhagic cystitis. In contrast, two of four consecutive patients who received mesna uroprophylaxis before allogeneic bone marrow transplantation had severe hemorrhagic cystitis for at least 2 weeks. Because of this suboptimal result, we resumed the use of bladder irrigation and forced hydration to minimize the risk of hemorrhagic cystitis.
In recipients of bone marrow transplants, the risk of hemorrhagic cystitis is usually minimized by treatment during conditioning with one or more uroprotective measures, including hydration, forced diuresis with or without urinary alkalinization, regular bladder drainage, or continuous bladder irrigation. Recently, 2-mercaptoethanesulfonate (mesna), a compound that neutralizes acrolein, has become commercially available. Acrolein, a hepatic metabolite of cyclophosphamide, is responsible for the hemorrhagic cystitis associated with cyclophosphamide therapy. Droller and associates! detected gross hematuria in 31 of 97 patients (32%) treated with cyclophosphamide (50 mg/kg per day for 4 days) without uroprophylaxis but in only 25 of 198 patients (13%) who were hydrated with 4 to 5 liters of 5% dextrose in saline and instructed to void frequently. Hows and colleagues? prospectively compared the efficacy of forced hydration and urinary alkalinization with the effectiveness of bolus injections of mesna (20 to 25 mg/kg) administered 30 minutes before cyclophosphamide therapy, 3, 6, and 9 hours after each treatment, and the day after the last dose of cyclophosphamide. Macroscopic hematuria
Address reprint requests to Dr. Louis Letendre, Division of Hematology, Mayo Clinic, Rochester, MN 55905. Mayo Clin Proc 67:128-130,1992
occurred in 9 of 26 patients (35%) in the forced diuresis group in comparison with 4 of 32 patients (12%) who received mesna. In a retrospective analysis of 125 patients, Ost and co-workers' found evidence of symptomatic hemorrhagic cystitis in 5 of 22 patients (23%) treated with alkaline diuresis, in 13 of 70 patients (19%) who received low-dose mesna (60 to 90% of the cyclophosphamide dose), and in 6 of 33 patients (18%) who received high-dose mesna (150% of the cyclophosphamide dose). Thomas and associates" noted 14 episodes of symptomatic hematuria after 78 bone marrow transplantation procedures in 65 patients. All these patients had received high-dose mesna, similar to the protocol reported by Hows and colleagues.' Numerous factors predispose to the occurrence of hemorrhagic cystitis. It is more common in recipients of allogeneic than autologous or syngeneic bone marrow transplants.' Ost and associates" reported that, in most of their patients, hemorrhagic cystitis developed concomitantly with the onset of graft-versus-host disease or with tapering of the dose of corticosteroids. Atkinson and colleagues" correlated the occurrence of hemorrhagic cystitis with specific conditioning regimens-it occurred more frequently after a regimen of busulfan and cyclophosphamide (in 7 of 15 patients) than after use of cyclophosphamide and total-body irradiation (in 14 of 111 patients). Hemorrhagic cystitis can also 128
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HEMORRHAGIC CYSTITIS AND MARROW TRANSPLANTATION
be caused by various infectious agents. Viruses such as cytomegalovirus, adenovirus, and influenza have all been implicated.?"
MATERIAL AND METHODS At our institution, the standard conditioning regimen for allogeneic bone marrow transplantation in patients with a neoplasm has been cyclophosphamide (60 mg/kg daily for 2 days) in conjunction with fractionated total-body irradiation (1,325 cGy twice daily for 3 days). In patients with aplastic anemia, we have administered cyclophosphamide in a dosage of 50 mg/kg daily for 4 days. All our patients have been prophylactically treated with forced hydration with use of saline (250 m1Jh) beginning 3 hours before administration of cyclophosphamide and continuous bladder irrigation with urologic saline (200 ml/h); both procedures are continued for 12 hours after completion of cyclophosphamide therapy. In an attempt to eliminate bladder irrigation, which is inconvenient for patients and a labor-intensive procedure, we initiated a feasibility trial during the spring of 1989 that consisted of forced hydration (similar to the aforementioned regimen) and a loading dose of mesna (10 mg/kg) at time 0, followed by continuous infusion of mesna (60 mglkg per 24 hours or 100% of the cyclophosphamide dose) for 48 hours. This schedule for administration of mesna was selected to avoid the potential risk of timing errors associated with bolus injections at specified intervals. The information on all patients undergoing bone marrow transplantation was prospectively collected in accordance with a predefined treatment protocol. Before transplantation, all patients underwent urinalysis and, if clinically indicated, urine culture. Both tests were repeated on the first urine sample after removal of the urinary catheter or 24 hours after the last infusion of cyclophosphamide and at the time of the first febrile episode, which usually occurred within the first week after transplantation. Additional urine specimens were examined as clinically indicated. Urine cytology for viral inclusion bodies and urine cultures for virus were not routinely performed. Clinically significant hemorrhagic cystitis was defined as an episode of symptomatic (burning, frequency, or dysuria) microscopic or macroscopic hematuria in the absence of bacterial cystitis or other clinical conditions, such as intravascular coagulation or sepsis. RESULTS Among the initial 97 patients who received standard prophylaxis, we noted 4 cases of symptomatic hemorrhagic cystitis (4%; 90% confidence interval, 1.1 to 8.5%). All four patients also had active graft-versus-host disease at the time of
129
onset of hemorrhagic cystitis. In one patient, the hemorrhagic cystitis subsided without treatment; the three other patients required hydration and continuous bladder irrigation before the hematuria resolved. Four consecutive patients who underwent allogeneic bone marrow transplantation received uroprophylaxis with mesna; busulfan and cyclophosphamide were used as a conditioning regimen in three of these patients, whereas the fourth patient received conventional cyclophosphamide and total-body irradiation. Severe hemorrhagic cystitis that persisted for 2 or more weeks developed in two patients, one of whom required bladder irrigation. Both patients had signs of graft-versus-host disease at the onset of their symptoms, and one patient had a urine culture that was positive for cytomegalovirus.
DISCUSSION Despite the fact that our report does not include prospectively randomized patients, the extremely low incidence of symptomatic hemorrhagic cystitis among our initial 97 patients is striking and compares favorably with other reported series. Two essential factors are careful insertion of the irrigation catheter to minimize trauma and diligent nursing supervision to record urinary output. Because our preliminary experience does not substantiate that uroprophylaxis with mesna is as effective as bladder irrigation, we have reverted to our standard prophylaxis with bladder irrigation, which has been associated with a low cost and minimal risk of hemorrhagic cystitis. ACKNOWLEDGMENT We acknowledge the work of Barbara A. Schafer, R.N., and all the paramedical personnel who devoted time and effort to the care of the patients in this study.
REFERENCES
1. Droller MJ, Sara! R, Santos G: Prevention of cyclophospha-
mide-induced hemorrhagic cystitis. Urology 20:256-258, 1982 2. Hows JM, MehtaA, WardL, Woods K, PerezR, Gordon MY, Gordon-Smith EC: Comparison of mesnawithforced diuresis to prevent cyclophosphamide induced haemorrhagic cystitis in marrow transplantation: a prospective randomised study. Br J Cancer 50:753-756, 1984 3. Ost L, Lonnqvist B, Eriksson L, Ljungman P, Ringden 0: Hemorrhagic cystitis-a manifestation of graftversus hostdisease? BoneMarrow Transplant 2:19-25,1987 4. Thomas AE, Patterson J, Prentice HG, Brenner MK, Ganczakowski M, Hancock JF, Pattinson JK, Blacklock HA, Hopewell JP: Haemorrhagic cystitis in bone marrow transplantation patients: possible increased risk associated with
130
HEMORRHAGIC CYSTITIS AND MARROW TRANSPLANTATION
prior busulphan therapy. Bone Marrow Transplant 1:347-355, 1987 5. Arthur RR, Shah KV, Baust SJ, Santos GW, Saral R: Association of BK viruria with hemorrhagic cystitis in recipients of bone marrow transplants. N Engl J Med 315:230-234, 1986 6. Atkinson K, Biggs J, Noble G, Ashby M, Concannon A, Dodds A: Preparative regimens for marrow transplantation containing busulphan are associated with haemorrhagic cystitis and hepatic veno-occlusive disease but a short duration of leucopenia
Mayo Clin Proc, February 1992, Vol 67
and little oro-pharyngeal mucositis. Bone Marrow Transplant 2:385-394,1987 7. Shields AF, Hackman RC, Fife KH, Corey L, Meyers JD: Adenovirus infections in patients undergoing bone-marrow transplantation. N Engl J Med 312:529-533,1985 8. Goldman RL, Warner NE: Hemorrhagic cystitis and cytomegalic inclusions in the bladder associated with cyclophosphamide therapy. Cancer 25:7-11, 1970 9. Khakpour M, Nik-Akhtar B: Epidemics of haemorrhagic cystitis due to influenza A virus. Postgrad Med J 53:251-253, 1977
LOUIS LETENDRE, M.D., H. CLARK HOAGLAND, M.D., MORIE A. GERTZ, M.D., Division of Hematology and Internal Medicine
Hemorrhagic cystitis is a potentially serious complication of high-dose cyclophosphamide therapy administered before bone marrow transplantation. As standard practice at our institution, patients who are scheduled to receive a bone marrow transplant are treated prophylactically with forced hydration and bladder irrigation. In an attempt to obviate the inconvenience of bladder irrigation, we conducted a feasibility trial of uroprophylaxis with mesna, which neutralizes the hepatic metabolite of cyclophosphamide that causes hemorrhagic cystitis. Of 97 patients who received standard prophylaxis, 4 had symptomatic hemorrhagic cystitis. In contrast, two of four consecutive patients who received mesna uroprophylaxis before allogeneic bone marrow transplantation had severe hemorrhagic cystitis for at least 2 weeks. Because of this suboptimal result, we resumed the use of bladder irrigation and forced hydration to minimize the risk of hemorrhagic cystitis.
In recipients of bone marrow transplants, the risk of hemorrhagic cystitis is usually minimized by treatment during conditioning with one or more uroprotective measures, including hydration, forced diuresis with or without urinary alkalinization, regular bladder drainage, or continuous bladder irrigation. Recently, 2-mercaptoethanesulfonate (mesna), a compound that neutralizes acrolein, has become commercially available. Acrolein, a hepatic metabolite of cyclophosphamide, is responsible for the hemorrhagic cystitis associated with cyclophosphamide therapy. Droller and associates! detected gross hematuria in 31 of 97 patients (32%) treated with cyclophosphamide (50 mg/kg per day for 4 days) without uroprophylaxis but in only 25 of 198 patients (13%) who were hydrated with 4 to 5 liters of 5% dextrose in saline and instructed to void frequently. Hows and colleagues? prospectively compared the efficacy of forced hydration and urinary alkalinization with the effectiveness of bolus injections of mesna (20 to 25 mg/kg) administered 30 minutes before cyclophosphamide therapy, 3, 6, and 9 hours after each treatment, and the day after the last dose of cyclophosphamide. Macroscopic hematuria
Address reprint requests to Dr. Louis Letendre, Division of Hematology, Mayo Clinic, Rochester, MN 55905. Mayo Clin Proc 67:128-130,1992
occurred in 9 of 26 patients (35%) in the forced diuresis group in comparison with 4 of 32 patients (12%) who received mesna. In a retrospective analysis of 125 patients, Ost and co-workers' found evidence of symptomatic hemorrhagic cystitis in 5 of 22 patients (23%) treated with alkaline diuresis, in 13 of 70 patients (19%) who received low-dose mesna (60 to 90% of the cyclophosphamide dose), and in 6 of 33 patients (18%) who received high-dose mesna (150% of the cyclophosphamide dose). Thomas and associates" noted 14 episodes of symptomatic hematuria after 78 bone marrow transplantation procedures in 65 patients. All these patients had received high-dose mesna, similar to the protocol reported by Hows and colleagues.' Numerous factors predispose to the occurrence of hemorrhagic cystitis. It is more common in recipients of allogeneic than autologous or syngeneic bone marrow transplants.' Ost and associates" reported that, in most of their patients, hemorrhagic cystitis developed concomitantly with the onset of graft-versus-host disease or with tapering of the dose of corticosteroids. Atkinson and colleagues" correlated the occurrence of hemorrhagic cystitis with specific conditioning regimens-it occurred more frequently after a regimen of busulfan and cyclophosphamide (in 7 of 15 patients) than after use of cyclophosphamide and total-body irradiation (in 14 of 111 patients). Hemorrhagic cystitis can also 128
Mayo Clin Proc, February 1992, Vol 67
HEMORRHAGIC CYSTITIS AND MARROW TRANSPLANTATION
be caused by various infectious agents. Viruses such as cytomegalovirus, adenovirus, and influenza have all been implicated.?"
MATERIAL AND METHODS At our institution, the standard conditioning regimen for allogeneic bone marrow transplantation in patients with a neoplasm has been cyclophosphamide (60 mg/kg daily for 2 days) in conjunction with fractionated total-body irradiation (1,325 cGy twice daily for 3 days). In patients with aplastic anemia, we have administered cyclophosphamide in a dosage of 50 mg/kg daily for 4 days. All our patients have been prophylactically treated with forced hydration with use of saline (250 m1Jh) beginning 3 hours before administration of cyclophosphamide and continuous bladder irrigation with urologic saline (200 ml/h); both procedures are continued for 12 hours after completion of cyclophosphamide therapy. In an attempt to eliminate bladder irrigation, which is inconvenient for patients and a labor-intensive procedure, we initiated a feasibility trial during the spring of 1989 that consisted of forced hydration (similar to the aforementioned regimen) and a loading dose of mesna (10 mg/kg) at time 0, followed by continuous infusion of mesna (60 mglkg per 24 hours or 100% of the cyclophosphamide dose) for 48 hours. This schedule for administration of mesna was selected to avoid the potential risk of timing errors associated with bolus injections at specified intervals. The information on all patients undergoing bone marrow transplantation was prospectively collected in accordance with a predefined treatment protocol. Before transplantation, all patients underwent urinalysis and, if clinically indicated, urine culture. Both tests were repeated on the first urine sample after removal of the urinary catheter or 24 hours after the last infusion of cyclophosphamide and at the time of the first febrile episode, which usually occurred within the first week after transplantation. Additional urine specimens were examined as clinically indicated. Urine cytology for viral inclusion bodies and urine cultures for virus were not routinely performed. Clinically significant hemorrhagic cystitis was defined as an episode of symptomatic (burning, frequency, or dysuria) microscopic or macroscopic hematuria in the absence of bacterial cystitis or other clinical conditions, such as intravascular coagulation or sepsis. RESULTS Among the initial 97 patients who received standard prophylaxis, we noted 4 cases of symptomatic hemorrhagic cystitis (4%; 90% confidence interval, 1.1 to 8.5%). All four patients also had active graft-versus-host disease at the time of
129
onset of hemorrhagic cystitis. In one patient, the hemorrhagic cystitis subsided without treatment; the three other patients required hydration and continuous bladder irrigation before the hematuria resolved. Four consecutive patients who underwent allogeneic bone marrow transplantation received uroprophylaxis with mesna; busulfan and cyclophosphamide were used as a conditioning regimen in three of these patients, whereas the fourth patient received conventional cyclophosphamide and total-body irradiation. Severe hemorrhagic cystitis that persisted for 2 or more weeks developed in two patients, one of whom required bladder irrigation. Both patients had signs of graft-versus-host disease at the onset of their symptoms, and one patient had a urine culture that was positive for cytomegalovirus.
DISCUSSION Despite the fact that our report does not include prospectively randomized patients, the extremely low incidence of symptomatic hemorrhagic cystitis among our initial 97 patients is striking and compares favorably with other reported series. Two essential factors are careful insertion of the irrigation catheter to minimize trauma and diligent nursing supervision to record urinary output. Because our preliminary experience does not substantiate that uroprophylaxis with mesna is as effective as bladder irrigation, we have reverted to our standard prophylaxis with bladder irrigation, which has been associated with a low cost and minimal risk of hemorrhagic cystitis. ACKNOWLEDGMENT We acknowledge the work of Barbara A. Schafer, R.N., and all the paramedical personnel who devoted time and effort to the care of the patients in this study.
REFERENCES
1. Droller MJ, Sara! R, Santos G: Prevention of cyclophospha-
mide-induced hemorrhagic cystitis. Urology 20:256-258, 1982 2. Hows JM, MehtaA, WardL, Woods K, PerezR, Gordon MY, Gordon-Smith EC: Comparison of mesnawithforced diuresis to prevent cyclophosphamide induced haemorrhagic cystitis in marrow transplantation: a prospective randomised study. Br J Cancer 50:753-756, 1984 3. Ost L, Lonnqvist B, Eriksson L, Ljungman P, Ringden 0: Hemorrhagic cystitis-a manifestation of graftversus hostdisease? BoneMarrow Transplant 2:19-25,1987 4. Thomas AE, Patterson J, Prentice HG, Brenner MK, Ganczakowski M, Hancock JF, Pattinson JK, Blacklock HA, Hopewell JP: Haemorrhagic cystitis in bone marrow transplantation patients: possible increased risk associated with
130
HEMORRHAGIC CYSTITIS AND MARROW TRANSPLANTATION
prior busulphan therapy. Bone Marrow Transplant 1:347-355, 1987 5. Arthur RR, Shah KV, Baust SJ, Santos GW, Saral R: Association of BK viruria with hemorrhagic cystitis in recipients of bone marrow transplants. N Engl J Med 315:230-234, 1986 6. Atkinson K, Biggs J, Noble G, Ashby M, Concannon A, Dodds A: Preparative regimens for marrow transplantation containing busulphan are associated with haemorrhagic cystitis and hepatic veno-occlusive disease but a short duration of leucopenia
Mayo Clin Proc, February 1992, Vol 67
and little oro-pharyngeal mucositis. Bone Marrow Transplant 2:385-394,1987 7. Shields AF, Hackman RC, Fife KH, Corey L, Meyers JD: Adenovirus infections in patients undergoing bone-marrow transplantation. N Engl J Med 312:529-533,1985 8. Goldman RL, Warner NE: Hemorrhagic cystitis and cytomegalic inclusions in the bladder associated with cyclophosphamide therapy. Cancer 25:7-11, 1970 9. Khakpour M, Nik-Akhtar B: Epidemics of haemorrhagic cystitis due to influenza A virus. Postgrad Med J 53:251-253, 1977
